Binding function 3 (bf3) site compounds as therapeutics and methods for their use

ABSTRACT

Uses of such compounds for treatment of various indications, including prostate cancer as well as methods of treatment involving such compounds are also provide.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 15/302,363, filed Oct. 6, 2016, which is a National Stage Application of International Patent Application No. PCT/CA2015/000239, filed Apr. 9, 2015; which claims the benefit of U.S. Provisional Patent Application Serial No. 61/977,445, filed Apr. 9, 2014 and U.S. Provisional Application No. 62/084,451, filed Nov. 25, 2014; all of which are incorporated herein by reference in their entireties.

TECHNICAL FIELD

This invention relates to therapeutics, their uses and methods for the treatment of various indications, including various cancers. In particular the invention relates to therapies and methods of treatment for cancers such as prostate cancer.

BACKGROUND

Androgens are known to mediate their effects through the androgen receptor (AR). Androgens play a role in a wide range of developmental and physiological responses, for example, male sexual differentiation, maintenance of spermatogenesis, and male gonadotropin regulation (R. K. Ross, G. A. Coetzee, C. L. Pearce, J. K. Reichardt, P. Bretsky, L. N. Kolonel, B. E. Henderson, E. Lander, D. Altshuler & G. Daley, Eur Urol 35, 355-361 (1999); A. A. Thomson, Reproduction 121, 187-195 (2001); N. Tanji, K. Aoki & M. Yokoyama, Arch Androl 47, 1-7 (2001)). Also, androgens are associated with the development of prostate carcinogenesis. Induction of prostatic carcinogenesis in rodent models has been associated with androgens (R. L. Noble, Cancer Res 37, 1929-1933 (1977); R. L. Noble, Oncology 34, 138-141 (1977)) and men receiving androgens in the form of anabolic steroids are reported to have a higher incidence of prostate cancer (J. T. Roberts & D. M. Essenhigh, Lancet 2, 742 (1986); J. A. Jackson, J. Waxman & A. M. Spiekerman, Arch Intern Med 149, 2365-2366 (1989); P. D. Guinan, W. Sadoughi, H. Alsheik, R. J. Ablin, D. Alrenga & I. M. Bush, Am J Surg 131, 599-600 (1976)). Furthermore, prostate cancer does not develop if humans or dogs are castrated before puberty (J. D. Wilson & C. Roehrborn, J Clin Endocrinol Metab 84, 4324-4331 (1999); G. Wilding, Cancer Sury 14, 113-130 (1992)). Castration of adult males causes involution of the prostate and apoptosis of prostatic epithelium (E. M. Bruckheimer & N. Kyprianou, Cell Tissue Res 301, 153-162 (2000); J. T. Isaacs, Prostate 5, 545-557 (1984)). This dependency on androgens provides the underlying rationale for treating prostate cancer with chemical or surgical castration (i.e. androgen ablation).

Prostate cancer is the second leading cause of male cancer-related death in Western countries (Damber, J. E. and Aus, G. Lancet (2008) 371:1710-1721). Numerous studies have shown that the androgen receptor (AR) is central not only to the development of prostate cancer, but also the progression of the disease to the castration resistance state (Taplin, M. E. et al. J. Clin. Oncol. (2003) 21:2673-8; and Tilley, W. D. et al. Cancer Res. (1994) 54:4096-4102). Thus, effective inhibition of human AR remains one of the most effective therapeutic approaches to the treatment of advanced, metastatic prostate cancer.

The AR possesses a modular organization characteristic of all nuclear receptors. It is comprised of an N-terminal domain, a central DNA binding domain, a short hinge region, and C-terminal domain that contains a hormone ligand binding pocket and the Activation Function-2 (AF2) site (Gao, W. Q. et al. Chem. Rev. (2005) 105:3352-3370). The latter represents a hydrophobic groove on the AR surface which is flanked with regions of positive and negative charges—“charge clamps” that are significant for binding AR activation factors (Zhou, X. E. et al. J. Biol. Chem. (2010) 285:9161-9171). Recent studies have identified a novel site on the AR called Binding Function 3 (BF3) that is involved into AR transcriptional activity.

It has been proposed a small molecule bound to the BF3 site could cause the AR protein to undergo an allosteric modification that prevents AR interactions with co-activators. Importantly, the BF3 site is located near, but distinct from, the ligand-binding site that is normally targeted by conventional anti-androgen drugs. Chemicals such as flufenamic acid (FLUF), thriiodothyronine (T3) and 3,3′,5-triiodo thyroacetic acid (TRIAC), can bind to the BF3 cleft, inhibit AF2 interactions and interfere with AR activity (Estebanez-Perpina, E. et al. Proc Natl Acad Sci USA (2007) 104:16074-16079). While these compounds revealed the importance of the BF3 site, they have shown a low potency (IC₅₀>50 μM) and were found to bind non-specifically to the AR.

The activation of AR follows a well characterized pathway: in the cytoplasm, the receptor is associated with chaperone proteins that maintain agonist binding conformation of the AR (Georget, V. et al. Biochemistry (2002) 41:11824-11831). Upon binding of an androgen, the AR undergoes a series of conformational changes, disassociation from chaperones, dimerization and translocation into the nucleus (Fang, Y. F. et al. J. Biol. Chem. (1996) 271:28697-28702; and Wong, C. I. et al. J. Biol. Chem. (1993) 268:19004-19012) where it further interacts with co-activator proteins at the AF2 site (Zhou, X. E. et al. J. Biol. Chem. (2010) 285:9161-9171). This event triggers the recruitment of RNA polymerase II and other factors to form a functional transcriptional complex with the AR.

Notably, the current anti-androgens such as bicalutamide, flutamide, nilutamide and MDV3100, all target this particular process. However, instead of affecting the AR-cofactor interaction directly, these anti-androgens act indirectly, by binding to the AR ligand binding site. Thus, by preventing androgens from binding they also prevent conformational changes of the receptor that are necessary for co-activator interactions. While treatment with these AR inhibitors can initially suppress the prostate cancer growth, long term hormone therapy becomes progressively less effective (Taplin, M. E. et al. J. Clin. Oncol. (2003) 21:2673-8; and Tilley, W. D. et al. Cancer Res. (1994) 54:4096-4102). Factors that make the AR less sensitive to conventional anti-androgens include resistance mutations at the ligand binding site that can even lead AR antagonists to act as agonists further contributing to cancer progression (Chen, Y. et al. Lancet Oncol. (2009) 10:981-991).

Androgens also play a role in female cancers. One example is ovarian cancer where elevated levels of androgens are associated with an increased risk of developing ovarian cancer (K. J. Helzlsouer, et al., JAMA 274, 1926-1930 (1995); R. J. Edmondson, et al, Br J Cancer 86, 879-885 (2002)). The AR has been detected in a majority of ovarian cancers (H. A. Risch, J Natl Cancer Inst 90, 1774-1786 (1998); B. R. Rao & B. J. Slotman, Endocr Rev 12, 14-26 (1991); G. M. Clinton & W. Hua, Crit Rev Oncol Hematol 25, 1-9 (1997)), whereas estrogen receptor-alpha (ERa) and the progesterone receptor are detected in less than 50% of ovarian tumors.

SUMMARY

This invention is based in part on the fortuitous discovery that compounds described herein modulate androgen receptor (AR) activity. Specifically, compounds identified herein, show inhibition of Androgen Receptor Binding Function-3 (BF3).

In accordance with a first aspect, there is provided a method of modulating AR activity, the method comprising administering a compound having the structure of Formula I:

wherein,

is either a single or a double bond between D₂ and D₃;

A₁ may be H, CH₃, CH₂CH₃, OH, CH₂OH, OCH₃,

Alternatively A₁ may be F, Br or Cl, provided that D₃ is not

A₂ may be H, Br, OH, Cl, F, I, CH₃, NH₂, OCH₃,

or ═O;

A₃ may be H, Br, NH₂, F, Cl, OCH₃, CH₃,

I, OH,

or ═O;

A₄ may be H, Br, Cl, F, I, CH₃, NH₂, OH, OCH₃,

or ═O;

D₁ is

wherein

E₁, E₈, E₁₄, E₁₆, E₂₂, E₃₀, and E₄₁, are each independently CH or N;

E₂, E₃, E₄, E₅, and E₆, are each independently H, OH,

Br, Cl, F, I, or CH₃;

E₇ is CH₂, O, NH, or C═O;

E₉, E₁₀, E₁₁, E₁₂, and E₁₃, are each independently H,

OH, Br, Cl, F, I, or CH₃;

E₁₅ is CH₂, O, NH, or C═O;

E₁₇, E₁₈, E₁₉, E₂₀, and E₂₁, are each independently H,

OH, Br, Cl, F, I, or CH₃;

E₂₃ is CH, CH₂, O, N, NH, or C═O;

where

is either a single or a double bond between E₂₂ and E₂₃;

E₂₄ is CH₂, O, NH, or C═O;

E₂₅, E₂₆, E₂₇, E₂₈, and E₂₉, are each independently H,

OH, Br, Cl, F, I, or CH₃;

E₃₁ is N, CH, CBr, CCl, CF, COH, C═O, or CCH₃;

E₃₂ is NH, CH₂, O, or S;

E₃₃, E₃₄, E₃₅, and E₃₆, are each independently H, OH,

Br, Cl, F, I, or CH₃;

E₃₇ is S, O, NH, CH₂, NCH₃,

C═O, N—N═O, N—CH₂—CH₂—OH, N—CH₂—C(O)—O—CH₂—CH₃,

N-E₃₈, CH-E₃₉,

E₃₈ is NH₂, O—CH₃, O—NH₂, CH₂—N═O, CH₂—CH₃, N(H)OH, C(O)—O—CH₂—CH₃, C—O—CH₃, C(O)—O—CH₃, C(O)—O—CH₂—CH₂—CH₃, C—O—CH₂—CH₂—CH₃, C(O)—CH₂—CH₂—CH₃, C(O)—O—CH₂—CH₃, or;

E₃₉ is CH₃, CH₂—CH₃, CH₂₋N═O, OH, OOH, NH₂, O—CH₃, O—NH₂, CH₂—N═O, CH₂—CH₃, N(H)OH, C(O)—O—CH₂—CH₃, C—O—CH₃, C(O)—O—CH₃, C(O)—O—CH₂—CH₂—CH₃, C—O—CH₂—CH₂—CH₃, C(O)—CH₂—CH₂—CH₃, or C(O)—O—CH₂—CH₃;

E₄₀ is CH₃, CH₂—CH₃, CH₂₋N═O, OH, OOH, NH₂, O—CH₃, O—NH₂, CH₂—N═O, CH₂—CH₃, N(H)OH, C(O)—O—CH₂—CH₃, C—O—CH₃, C(O)—O—CH₃, C(O)—O—CH₂—CH₂—CH₃, C—O—CH₂—CH₂—CH₃, C(O)—CH₂—CH₂—CH₃, or C(O)—O—CH₂—CH₃;

E₄₂, E₄₃, E₄₄, E₄₅, and E₄₆, are each independently H,

OH, Br, Cl, F, I, or CH₃;

D₂ is

G₁ is CH, N, CCH₃, CH₂,

O, S, or NH;

G₂ is C, CH, or N;

G₃ is CH,

CH₂, or N;

G₄ is

G₅, G₆, and G₇, are each independently H, OH, Br, Cl, F, I, or CH₃;

G₈ is NH, CH₂, O, or S;

G₉, G₁₀, G₁₁, and G₁₂, are each independently H, OH, Br, Cl, F, I, or CH₃;

G₁₃ is C, CH, or N;

G₁₄ is C═O, CH₂, or NH;

G₁₅ is C═O, CH₂, or NH;

G₁₆ is

G₁₇, G₁₈, G₁₉, G₂₀, and G₂₁, are each independently H, OH, Br, Cl, F, I, or CH₃, provided that if G₁₇ is OH, then one or more of G₁₈, G₁₉, G₂₀, and G₂₁ are selected from OH, Br, Cl, F, I, or CH₃;

G₂₂ is NH, CH₂, O, or S;

G₂₃, G₂₄, G₂₅, and G₂₆, are each independently H, OH, Br, Cl, F, I, or CH₃;

G₂₇ is C, CH, CCH₃, CC(O)OCH₂CH₃, or N;

G₂₈ is C, CH, or N;

G₂₉ is CH, CH₂, C═O, CCH₃, or N;

where

is either a single or a double bond between G₂₈ and G₂₉;

G₃₀ is CH₂, N—N═O, NCH₃, NCH₂CH₂OH, CH—N═O, CHCH₃, CHCH₂CH₂OH, S, O,

or NH;

G₃₁, G₃₂, and G₃₃, are each independently H, OH, NH₂, Br, Cl, F, I,

OCH₃,

CH₃, CH₂OH, or absent when G₃₆, G₃₇, or G₃₈ is N;

G₃₄, is H, OH, NH₂,

OCH₃, CH₃, CH₂OH, I or absent when G₃₅ is N;

G₃₅, G₃₆, G₃₇, and G₃₈, are each independently C or N;

G₃₉ is C, CH, or N;

G₄₀ is CH, or N;

G₄₁ is NH, S, O, or CH₂;

G₄₂, G₄₃, G₄₄, and G₄₅, are each independently H, OH, Br, Cl, F, I, or CH₃;

G₄₆ is C, CH, or N;

G₄₇, G₄₈, G₅₀, and G₅₁, are each independently H, OH, Br, Cl, F, I, or CH₃;

G₄₉ is OH, Br, Cl, F, I or CH₃;

G₅₂ is C, CH, or N;

G₅₃ is CH₂, NH, S, or O;

G₅₄, G₅₅, G₅₆, G₅₇, and G₅₈, are each independently H, OH, Br, Cl, F, I, or CH₃;

D₃ may be

D₃ may be

Alternatively, D₃ may be

provided that A₁ is H, CH₃, F, Cl or Br and A₂ is H, CH₃, NH₂, OH or OCH₃, A₃ is H, F, Cl or Br and A₄ is H, F, Cl or Br.

Alternatively, D₃ may be

provided A₁ is CH₃, A₂ is F, A₃ is H and A₄ is H.

Alternatively, D₃ may be

provided that at least one of A₁, A₃ or A₄ is F, Cl or Br and A₂ is H, CH₃, NH₂, OH or OCH₃.

Alternatively, D₃ may be

provided that at least one of A₂ or A₃ is F, Cl or Br.

Alternatively, D₃ may be

provided that A₄ is H.

Alternatively, D₃ may be

provided that A₁ is CH₃.

Alternatively, D₃ may be

provided that at least one of A₁ or A₂ is F, Cl, Br or CH₃.

Alternatively, D₃ may be

provided that if A₂ is F, Cl or Br then A₃ is F, Cl or Br.

Alternatively, D₃ may be

provided that if A₂ is F, Cl or Br then A₁ is H, OH, CH₂OH,

CF₃, F, Cl or Br, A₃ is H, Br, NH₂, F, Cl, OCH₃,

CF₃, I, OH,

or ═O and A₄ is H, Br, Cl, F, I, CH₃, NH₂, OH, OCH₃,

CF₃,

or ═O.

Alternatively, D₃ may be

provided that if A₂ is F, Cl or Br then A₁ is not CH₃.

Alternatively, D₃ may be

provided that if A₂ is F, Cl or Br then A₁ is not CH₃.

Alternatively, D₃ may be

provided that if A₂ is F, Cl or Br then at least one or both of A₁ and A₃ are F, Cl or Br.

Alternatively, D₃ may be

provided that if A₁ is CH₃ then A₂ is not F, Br or Cl.

Alternatively, D₃ may be

provided that if A₁ is CH₃ then A₂ is H.

Alternatively, D₃ may be

provided that A₁ is F, Br or Cl.

Alternatively, D₃ is

provided that A₁-A₄ are all H.

Alternatively, D₃ may be

provided that if A₄ is CH₃, then A₁ is CH₂OH,

CF₃, F, Cl or Br, A₂ is Br, NH₂, F, Cl,

CF₃, I or

and A₃ is Br, Cl, F, I, CH₃, NH₂,

CF₃,

or ═O.

Alternatively, D₃ may be

provided that A₄ is H, and A₁₋₄ are independently selected from Br, Cl, F, I, CH₃, NH₂,

CF₃,

or ═O.

Alternatively, D₃ may be

provided that A₂ is F and A₃ is F.

Alternatively, D₃ may be

provided that A₂ is F, Cl or Br and A₃ is F, Cl or Br.

Alternatively, D₃ may be

provided that A₁ is F, A₃ is F and A₄ is F.

Alternatively, D₃ may be

provided that A₁ is F, Cl or Br, A₃ is F, Cl or Br and A₄ is F, Cl or Br.

Alternatively, D₃ may be

provided that A₁ is F, Cl or Br, A₃ is F, Cl or Br and A₄ is F, Cl or Br.

Alternatively, D₃ is

provided that A₂ is H, if A₁ is CH₃.

J₁ is CH, N, CCH₃, CH₂, NCH₃, CN═O, C═O,

N—CH₂—CH₂—CH₃, CH═O, N—N═O,

NCH₂C(O)OCH₂CH₃, N—CH₂—C(O)—O—CH₂—CH₃, O, S, or NH.

J₂ is CH, C, or N.

J₃ is C═S, C═O, NH, or CH₂.

J₄ is CH or N;

J₅ is CH₂, NH, S or O;

J₆, J₇, J₈, J₉, J₁₀, J₁₁, J₁₂, and J₁₃ are each independently H, OH, Br, Cl, F, I, or CH₃;

J₁₄ is CH, C, or N;

J₁₅ is C═S, C═O, NH, or CH₂;

J₁₆ , J₁₇, J₁₈, J₁₉, and J₂₀ are each independently H, OH, Br, Cl, F, I,

or CH₃;

J₂₁ is CH, C, or N;

J₂₂ is CH₂, or NH;

J₂₃ is CH, or N;

J₂₄, J₂₅, J₂₆, and J₂₇ are each independently H, OH, Br, Cl, F, I, or CH₃;

J₂₈ is CH, C, or N;

J₃₁ is H, OH, Br, F, I, C(O)NH₂, OCH₃, or CH₃;

J₂₉, J₃₀, J₃₂, and J₃₃ are each independently H, OCH₃, OH, Br, Cl, F, I, C(O)NH₂, CF₃,

NH₂, or CH₃;

J₃₄ is CH, C, or N;

J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ are each independently H, OCH₃, OH, Br, Cl, F, I, C(O)NH₂, CF₃,

NH₂, or CH₃;

J₄₀ is CH, C, or N;

J₄₁ is H, OH, Br, Cl, F, I, NH₂, or CH₃, or

J₄₂, J₄₃, J₄₄, J₄₅, and J₄₆ are each independently H, OH, Br, Cl, F, I, NH₂, or CH₃;

J₄₇ is CH, C, or N;

J₄₈ is S, CH₂, C═O, O, or NH;

J₄₉ is CH₂, C═O, S, O, or NH;

J₅₅ is C, or N;

J₅₀, J₅₁, J₅₂, J₅₃, and J₅₄, are each independently H, OH, NH₂, Br, Cl, F, I,

OCH₃, CF₃, CH₃ or is absent when J₅₀, J₅₁, J₅₂, J₅₃, or J₅₄ is N;

J₅₆ is CH, C, or N;

J₅₇ is N, or CH;

J₅₈, J₅₉, J₆₀, J₆₁, and J₆₂, are each independently H, OH, NH₂, Br, Cl, F, I,

OCH₃, CF₃, or CH₃;

J₆₃, J₆₄, J₆₅, J₆₆, and J₆₇, are each independently H, OH, NH₂, Br, Cl, F, I,

OCH₃, CF₃, or CH₃;

J₆₃ is CH, C, or N;

J₆₄ is CH, CH₂, NH, CN═O, C═O, O, CCH₃, NCH₃, NC(O)OCH₃,

or N;

J₆₅ is CH₂, NH, C═O, O, S, NN═O, NCH₃, NC(O)OCH₃,

J₆₆, J₆₇, J₆₈, and J₆₉ may each independently be H, OCH₃, OH, Br, Cl, F, I, C(O)NH₂, CF₃,

NH₂, or CH₃;

J₇₀ is CH, C, or N;

J₇₁, J₇₂, J₇₃, and J₇₄ may each independently be H, OCH₃, OH, Br, Cl, F, I, C(O)NH₂, CF₃,

NH₂, or CH₃;

J₇₅ may be CH, or N;

J₇₇ is

and

provided that one or more of D₁-D₃ links to at least one ring in addition to the bicyclic structure of Formula I. For example, compounds 13720-13726, do not link to at least one ring in addition to the bicyclic structure of Formula I, whereas, for example, 13566 and 13742 do link to at least one ring in addition to the bicyclic structure of Formula I.

In accordance with a further aspect, there is provided a use of a compound having the structure of Formula I as described herein for modulating AR activity.

In accordance with a further aspect, there is provided a use of a compound having the structure of Formula I as described herein for the manufacture of a medicament for modulating AR activity.

A₁ may be H, CH₃, CH₂CH₃, OH, CH₂OH, OCH₃,

or CF₃. Alternatively A₁ may be F, Br or Cl, provided that D₃ is not

A₁ may be H, CH₃, OH, CH₂OH, OCH₃,

or CF₃. A₁ may be H, CH₃, OH, CH₂OH, OCH₃, or

A₁ may be H, CH₃, OH, CH₂OH, or OCH₃. A₁ may be H, CH₃, OH, CH₂OH, or

A₂ may be H, Br, OH, Cl, F, I, CH₃, NH₂, OCH₃,

CF₃,

or ═O. A₂ may be H, Br, OH, Cl, or

A₂ may be H, Br, OH, Cl, F, I, CH₃, NH₂, OCH₃ or ═O. A₂ may be H, Br, OH, Cl, F, I, CH₃, NH₂ or OCH₃. A₂ may be H, Br, OH, or Cl. A₂ may be H, Br, OH, Cl, or F.

A₃ may be H, Br, NH₂, F, Cl, OCH₃, CH₃,

CF₃, I, OH,

or ═O. A₃ may be H, Br, NH₂, F, Cl, OCH₃, CH₃,

or CF₃. A₃ may be H, Br, NH₂, F, Cl, OCH₃, CH₃, OH or ═O. A₃ may be H, Br, NH₂, F, Cl, OCH₃, CH₃,

CF₃, or ═O. A₃ may be H, Br, NH₂, F, Cl, OCH₃, CH₃,

CF₃, OH or ═O. A₃ may be H, Br, NH₂, F, Cl, OCH₃, CH₃, OH or ═O. A₃ may be H, Br, NH₂, F, Cl, OCH₃, or CH₃.

A₄ may be H, Br, Cl, F, I, CH₃, NH₂, OH, OCH₃,

CF₃,

or ═O. A₄ may be H, Br. A₄ may be H, Br, Cl, F, I, CH₃, NH₂, OH, OCH₃ or ═O. A₄ may be H, Br, Cl, F, CH₃, NH₂, OH, OCH₃, or ═O. A₄ may be H, Br, Cl, F, I, CH₃, NH₂, OH or OCH₃. A₄ may be H, Br, Cl, CH₃, NH₂, OH, OCH₃,

CF₃,

or ═O.

D₁ may be

D₁ may be

E₁, E₈, E₁₄, E₁₆, E₂₂, E₃₀, and E₄₁, may each independently be CH or N. E₁, E₈, E₁₄, E₁₆, E₂₂, E₃₀, and E₄₁, may be N. E₁, E₈, E₁₄, E₁₆, E₂₂, E₃₀, and E₄₁, may be CH.

E₂, E₃, E₄, E₅, and E₆, may each independently be H, OH,

Br, Cl, F, I, or CH₃. E₂, E₃, E₄, E₅, and E₆, may each independently be H, OH, or

E₂, E₃, E₄, E₅, and E₆, may each independently be H or OH.

E₇ may be CH₂, O, NH, or C═O. E₇ may be CH₂. E₇ may be CH₂, O or C═O. E₇ may be CH₂ or O. E₇ may be CH₂, O, NH or C═O. E₇ may be CH₂, NH or C═O.

E₉, E₁₀, E₁₁, E₁₂, and E₁₃, may each independently be H,

OH, Br, Cl, F, I or CH₃. E₉, E₁₀, E₁₁, E₁₂, and E₁₃, may each independently be H or

E₉, E₁₀, E₁₁, E₁₂, and E₁₃, may each independently be H, OH, Br, Cl, F, I or CH₃. E₉, E₁₀, E₁₁, E₁₂, and E₁₃, may each independently be H,

OH, Br, Cl, F, or CH₃. E₉, E₁₀, E₁₁, E₁₂, and E₁₃, may each independently be H, OH, or CH₃. E₉, E₁₀, E₁₁, E₁₂, and E₁₃, may each independently be H or CH₃.

E₁₅ may be CH₂, O, NH or C═O. E₁₅ may be NH. E₁₅ may be CH₂, O or NH. E₁₅ may be O, NH, or C═O. E₁₅ may be NH or C═O.

E₁₇, E₁₈, E₁₉, E₂₀, and E₂₁, may each independently be H,

OH, Br, Cl, F, I, or CH₃. E₁₇, E₁₈, E₁₉, E₂₀, and E₂₁, may each independently be H, OH, Br, Cl, F, I or CH₃. E₁₇, E₁₈, E₁₉, E₂₀, and E₂₁, may each independently be H, Cl, or CH₃. E₁₇, E₁₈, E₁₉, E₂₀, and E₂₁, may each independently be H, OH, Br, Cl, F or CH₃.

E₂₃ may be CH, CH₂, O, N, NH, or C═O. E₂₃ may be N. E₂₃ may be O, N, NH, or C═O. E₂₃ may be CH, CH₂, O, N or NH. E₂₃ may be N or NH.

E₂₄ may be CH₂, O, NH, or C═O. E₂₄ may be NH. E₂₄ may be CH₂, NH, or C═O. E₂₄ may be O or NH. E₂₄ may be CH₂, O or NH. E₂₄ may be NH, or C═O. E₂₄ may be CH₂ or NH.

E₂₅, E₂₆, E₂₇, E₂₈, and E₂₉, may each independently be H,

OH, Br, Cl, F, I, or CH₃. E₂₅, E₂₆, E₂₇, E₂₈, and E₂₉, may each independently be H, OH, Br, Cl, F, I or CH₃. E₂₅, E₂₆, E₂₇, E₂₈, and E₂₉, may each independently be H or Cl. E₂₅, E₂₆, E₂₇, E₂₈, and E₂₉, may each independently be H, OH, Br, Cl, F, or CH₃. E₂₅, E₂₆, E₂₇, E₂₈, and E₂₉, may each independently be H, OH, Cl or CH₃. E₂₅, E₂₆, E₂₇, E₂₈, and E₂₉, may each independently be H or CH₃. E₂₅, E₂₆, E₂₇, E₂₈, and E₂₉, may each independently be H, Br, Cl or CH₃.

E₃₁ may be N, CH, CBr, CCl, CF, COH, C═O, or CCH₃. E₃₁ may be N. E₃₁ may be N, CH, COH, C═O, or CCH₃. E₃₁ may be N, CH, CCl, COH, C═O, or CCH₃. E₃₁ may be N, CH, COH or CCH₃.

E₃₂ may be NH, CH₂, O, or S. E₃₂ may be NH or O. E₃₂ may be NH, CH₂ or O. E₃₂ may be NH. E₃₂ may be O. E₃₂ may be NH, O or S.

E₃₃, E₃₄, E₃₅, and E₃₆, may each independently be H, OH,

Br, Cl, F, I, or CH₃. E₃₃, E₃₄, E₃₅, and E₃₆, may each independently be H, OH, Br, Cl, F, I or CH₃. E₃₃, E₃₄, E₃₅, and E₃₆, may each independently be H, OH,

or CH₃. E₃₃, E₃₄, E₃₅, and E₃₆, may each independently be H, OH or CH₃.

E₃₇ may be S, O, NH, CH₂, NCH₃,

C═O, N—N═O, N—CH₂—CH₂—OH, N—CH₂—C(O)—O—CH₂—CH₃,

N-E₃₈, CH-E₃₉,

E₃₇ may be S, O, NH, CH₂, NCH₃,

C═O, N—N═O, N—CH₂—CH₂—OH, N—CH₂—C(O)—O—CH₂—CH₃ or

E₃₇ may be S, O, NH, CH₂, NCH₃,

C═O, N—N═O, N—CH₂—CH₂—OH, N—CH₂—C(O)—O—CH₂—CH₃,

E₃₇ may be S, O, NH, CH₂, NCH₃,

C═O, N—N═O, N—CH₂—CH₂—OH, or N—CH₂—C(O)—O—CH₂—CH₃.

E₃₈ may be NH₂, O—CH₃, O—NH₂, CH₂—N═O, CH₂—CH₃, N(H)OH, C(O)—O—CH₂—CH₃, C—O—CH₃, C(O)—O—CH₃, C(O)—O—CH₂—CH₂—CH₃, C—O—CH₂—CH₂—CH₃, C(O)—CH₂—CH₂—CH₃, C(O)—O—CH₂—CH₃, or

E₃₈ may be NH₂, O—CH₃ or O—NH₂. E₃₈ may be NH₂ or O—CH₃.

E₃₉ may be CH₃, CH₂—CH₃, CH₂₋N═O, OH, OOH, NH₂, O—CH₃, O—NH₂, CH₂—N═O, CH₂—CH₃, N(H)OH, C(O)—O—CH₂—CH₃, C—O—CH₃, C(O)—O—CH₃, C(O)—O—CH₂—CH₂—CH₃, C—O—CH₂—CH₂—CH₃, C(O)—CH₂—CH₂—CH₃ or C(O)—O—CH₂—CH₃. E₃₉ may be CH₃, CH₂—CH₃, CH₂₋N═O, OH, OOH, NH₂, O—CH₃, O—NH₂, CH₂—N═O, or CH₂—CH₃. E₃₉ may be CH₃, CH₂—CH₃, OH, OOH, NH₂, O—CH₃, O—NH₂, C—O—CH₃ or C(O)—O—CH₃.

E₄₀ may be CH₃, CH₂—CH₃, CH₂₋N═O, OH, OOH, NH₂, O—CH₃, O—NH₂, CH₂—N═O, CH₂—CH₃, N(H)OH, C(O)—O—CH₂—CH₃, C—O—CH₃, C(O)—O—CH₃, C(O)—O—CH₂—CH₂—CH₃, C—O—CH₂—CH₂—CH₃, C(O)—CH₂—CH₂—CH₃, or C(O)—O—CH₂—CH₃. E₄₀ may be CH₃, CH₂—CH₃, CH₂₋N═O, OH, OOH, NH₂, O—CH₃ or O—NH₂.

E₄₂, E₄₃, E₄₄, E₄₅, and E₄₆, may each independently be H,

OH, Br, Cl, F, I or CH₃. E₄₂, E₄₃, E₄₄, E₄₅, and E₄₆, may each independently be H, OH, Cl, or CH₃. E₄₂, E₄₃, E₄₄, E₄₅, and E₄₆, may each independently be H or Cl. E₄₂, E₄₃, E₄₄, E₄₅, and E₄₆, may each independently be H, Cl, or CH₃. E₄₂, E₄₃, E₄₄, E₄₅, and E₄₆, may each independently be H, OH or Cl.

D₂ may be

D₂ may be

D₂ may be

G₁ may be CH, N, CCH₃, CH₂,

O, S, or NH. G₁ may be CH, N, CCH₃, CH₂, or

G₁ may be CH, N, CCH₃, CH₂,

G₁ may be CH, N, CCH₃, CH₂, O, S, or NH. G₁ may be CH, N, CCH₃ or CH₂.

G₂ may be C, CH, or N. G₂ may be C. G₂ may be C. G₂ may be C or CH. G₂ may be C or N.

G₃ may be CH,

CH₂, or N. G₃ may be CH,

G₃ may be CH, CH₂ or N. G₃ may be CH.

G₄ may be

G₄ may be

G₄ may be

G₅, G₆, and G₇, may each independently be H, OH, Br, Cl, F, I, or CH₃. G₅, G₆, and G₇, may each independently be H or CH₃. G₅, G₆, and G₇, may each independently be H, OH, or CH₃. G₅, G₆, and G₇, may each independently be H, Br, Cl, F, or CH₃. G₅, G₆, and G₇, may each independently be H, OH, Br, CH₃.

G₈ may be NH, CH₂, O, or S. G₈ may be NH. G₈ may be NH, O, or S. G₈ may be NH, CH₂, or S. G₈ may be NH or S. G₈ may be NH or CH₂.

G₉, G₁₀, G₁₁, and G₁₂, may each independently be H, OH, Br, Cl, F, I or CH₃. G₉, G₁₀, G₁₁, and G₁₂, may each independently be H or Br. G₉, G₁₀, G₁₁, and G₁₂, may each independently be H, OH, Br, Cl or F. G₉, G₁₀, G₁₁, and G₁₂, may each independently be H, OH, Br, Cl, F or CH₃. G₉, G₁₀, G₁₁, and G₁₂, may each independently be H, OH or Br.

G₁₃ may be C, CH, or N. G₁₃ may be C or N. G₁₃ may be N. G₁₃ may be C.

G₁₄ may be C═O, CH₂, or NH. G₁₄ may be NH. G₁₄ may be CH₂. G₁₄ may be NH.

G₁₅ may be C═O, CH₂, or NH. G₁₅ may be C═O. G₁₅ may be CH₂. G₁₅ may be NH.

G₁₆ may be

G₁₆ may be

G₁₆ may be

G₁₇, G₁₈, G₁₉, G₂₀, and G₂₁, are each independently H, OH, Br, Cl, F, I, or CH₃, provided that if G₁₇ is OH, then one or more of G₁₈, G₁₉, G₂₀, and G₂₁ are selected from OH, Br, Cl, F, I, or CH₃.

G₂₂ may be NH, CH₂, O, or S. G₂₂ may be NH. G₂₂ may be NH or S. G₂₂ may be NH, O or S. G₂₂ may be NH or CH₂. G₂₂ may be NH, O, or S. G₂₂ may be NH or O.

G₂₃, G₂₄, G₂₅, and G₂₆, may each independently be H, OH, Br, Cl, F, I or CH₃. G₂₃, G₂₄, G₂₅, and G₂₆, may each independently be H or Br. G₂₃, G₂₄, G₂₅, and G₂₆, may each independently be H, OH, Br, Cl, F, or CH₃. G₂₃, G₂₄, G₂₅, and G₂₆, may each independently be H, Br, Cl, F or I. G₂₃, G₂₄, G₂₅, and G₂₆, may each independently be H, OH, Br or CH₃.

G₂₇ may be C, CH, CCH₃, CC(O)OCH₂CH₃, or N. G₂₇ may be C, CH, CCH₃ or CC(O)OCH₂CH₃. G₂₇ may be C. G₂₇ may be CH. G₂₇ may be CCH₃. G₂₇ may be CC(O)OCH₂CH₃.

G₂₈ may be C, CH, or N. G₂₈ may be C or N. G₂₈ may be C. G₂₈ may be N.

G₂₉ may be CH, CH₂, C═O, CCH₃, or N. G₂₉ may be CH. G₂₉ may be CH₂. G₂₉ may be C═O, CCH₃.

G₃₀ may be CH₂, N—N═O, NCH₃, NCH₂CH₂OH, CH—N═O, CHCH₃, CHCH₂CH₂OH, S, O,

or NH. G₃₀ may be CH₂, N—N═O, NCH₃, NCH₂CH₂OH,

or NH. G₃₀ may be CH₂, N—N═O, NCH₃, NCH₂CH₂OH, CH—N═O, CHCH₃, CHCH₂CH₂OH, S, O, or NH. G₃₀ may be CH₂, N—N═O, NCH₃, NCH₂CH₂OH, or NH.

G₃₁, G₃₂, and G₃₃, may each independently be H, OH, NH₂, Br, Cl, F, I,

OCH₃, CF₃, CH₃, CH₂OH, or absent when G₃₆, G₃₇, or G₃₈ is N. G₃₁, G₃₂, and G₃₃, may each independently be H, OH, NH₂, Br, Cl, F, I,

OCH₃, CF₃, CH₃, CH₂OH, or absent when G₃₆, G₃₇, or G₃₈ is N. G₃₁, G₃₂, and G₃₃, may each independently be H, OH, NH₂, Br, Cl, F, OCH₃, CH₃, CH₂OH, or absent when G₃₆, G₃₇, or G₃₈ is N.

G₃₄, may be H, OH, NH₂,

OCH₃, CH₃, CH₂OH, I or absent when G₃₅ is N. G₃₄, may be H, OH, NH₂,

OCH₃, CH₃, CH₂OH, or absent when G₃₅ is N. G₃₄, may be H, OH, NH₂, OCH₃, CH₃, CH₂OH, or absent when G₃₅ is N.

G₃₅, G₃₆, G₃₇, and G₃₈, may each independently be C or N. G₃₅, G₃₆, G₃₇, and G₃₈, may each be N. G₃₅, G₃₆, G₃₇, and G₃₈, may each be C.

G₃₉ may be C, CH or N. G₃₉ may be C. G₃₉ may be C or CH. G₃₉ may be C or N.

G₄₀ may be CH, or N. G₄₀ may be N. G₄₀ may be CH.

G₄₁ may be NH, S, O, or CH₂. G₄₁ may be NH, S or O. G₄₁ may be NH. G₄₁ may be S.

G₄₂, G₄₃, G₄₄, and G₄₅, may each independently be H, OH, Br, Cl, F, I or CH₃. G₄₂, G₄₃, G₄₄, and G₄₅, may each independently be H or Br. G₄₂, G₄₃, G₄₄, and G₄₅, may each independently be H, OH, Br or CH₃.

G₄₆ may be C, CH, or N. G₄₆ may be C. G₄₆ may be C or N. G₄₆ may be CH or N.

G₄₇, G₄₈, G₅₀, and G₅₁, are each independently be H, OH, Br, Cl, F, I or CH₃. G₄₇, G₄₈, G₅₀, and G₅₁, are each independently be H or OH. G₄₇, G₄₈, G₅₀, and G₅₁, are each independently be H, OH or CH₃. G₄₇, G₄₈, G₅₀, and G₅₁, are each be H. G₄₇, G₄₈, G₅₀, and G₅₁, are each independently be OH. G₄₉ is OH, Br, Cl, F, I or CH₃. G₄₉ is Br, Cl, F or I. G₄₉ is OH or CH₃.

G₅₂ may be C, CH or N. G₅₂ may be C. G₅₂ may be C or N. G₅₂ may be C or CH.

G₅₃ may be CH₂, NH, S or O. G₅₃ may be NH. G₅₃ may be CH₂ or NH. G₅₃ may be NH or O. G₅₃ may be NH or S.

G₅₄, G₅₅, G₅₆, G₅₇, and G₅₈, may each independently be H, OH, Br, Cl, F, I or CH₃. G₅₄, G₅₅, G₅₆, G₅₇, and G₅₈, may each independently be H, Cl or F. G₅₄, G₅₅, G₅₆, G₅₇, and G₅₈, may each be H. G₅₄, G₅₅, G₅₆, G₅₇, and G₅₈, may each be Cl. G₅₄, G₅₅, G₅₆, G₅₇, and G₅₈, may each be F. G₅₄, G₅₅, G₅₆, G₅₇, and G₅₈, may each independently be H, Br, Cl, F or CH₃.

D₃ may be

D₃ may be

D₃ may be

J₁ may be CH, N, CCH₃, CH₂, NCH₃, CN═O, C═O,

N—CH₂—CH₂—CH₃, CH═O, N—N═O,

NCH₂C(O)OCH₂CH₃, N—CH₂—C(O)—O—CH₂—CH₃, O, S or NH. J₁ may be CH, N, CH₂, NCH₃, CN═O, C═O,

or NH. J₁ may be CH, N, CCH₃, CH₂, NCH₃, CN═O, C═O,

O, S or NH. J₂ may be CH, C, or N. J₂ may be CH. J₂ may be CH or C. J₂ may be CH, or N. J₃ may be C═S, C═O, NH, or CH₂. J₃ may be C═S. J₃ may be C═S or CH₂. J₃ may be C═S or C═O. J₃ may be C═S or NH. J₄ may be CH or N. J₄ may be N. J₄ may be CH. J₅ may be CH₂, NH, S or O. J₅ may be O. J₅ may be CH₂ or O. J₅ may be NH, S or O. J₅ may be S or O. J₅ may be NH or O. J₆, J₇, J₈, J₉, J₁₀, J₁₁, J₁₂, and J₁₃ may each independently be H, OH, Br, Cl, F, I or CH₃. J₆, J₇, J₈, J₉, J₁₀, J₁₁, J₁₂, and J₁₃ may each independently be H. J₆, J₇, J₈, J₉, J₁₀, J₁₁, J₁₂, and J₁₃ may each independently be H, OH, Br, Cl, F or CH₃. J₁₄ may be CH, C, or N. J₁₄ may be N. J₁₄ may be CH or N. J₁₄ may be C or N. J₁₅ may be C═S, C═O, NH or CH₂. J₁₅ may be CH₂. J₁₅ may be NH or CH₂. J₁₅ may be C═S or CH₂. J₁₅ may be C═O or CH₂.

J₁₆, J₁₇, J₁₈, J₁₉, and J₂₀ may each independently be H, OH, Br, Cl, F, I,

or CH₃. J₁₆, J₁₇, J₁₈, J₁₉, and J₂₀ may each independently be H or

J₁₆, J₁₇, J₁₈, J₁₉, and J₂₀ may each independently be H, OH, Br, Cl, F,

or CH₃. J₂₁ may be CH, C or N. J₂₁ may be CH. J₂₁ may be CH or N. J₂₁ may be CH or C. J₂₂ may be NH. J₂₂ may be CH₂. J₂₂ may be CH₂ or NH. J₂₃ may be CH or N. J₂₃ may be CH. J₂₃ may be N. J₂₄, J₂₅, J₂₆, and J₂₇ may each independently be H, OH, Br, Cl, F, I or CH₃. J₂₄, J₂₅, J₂₆, and J₂₇ may each independently be H. J₂₄, J₂₅, J₂₆, and J₂₇ may each independently be H, OH or CH₃. J₂₄, J₂₅, J₂₆, and J₂₇ may each independently be H, OH, Br, Cl or CH₃. J₂₈ may be CH, C or N. J₂₈ may be C. J₂₈ may be CH or C. J₂₈ may be C or N. J₃₁ may be H, OH, Br, F, I, C(O)NH₂, OCH₃ or CH₃. J₃₁ may be H, Br, OCH₃ or CH₃. J₃₁ may be H, OH, Br, Cl, F, I, C(O)NH₂, OCH₃ or CH₃. J₃₁ may be Cl. J₃₁ may be H. J₃₁ may be Br. J₃₁ may be OCH₃. J₃₁ may be CH₃. J₂₉, J₃₀, J₃₂, and J₃₃ may each independently be H, OCH₃, OH, Br, Cl, F, I, C(O)NH₂, CF₃,

NH₂, or CH₃. J₂₉, J₃₀, J₃₂, and J₃₃ may each independently be H, OH, Br, Cl, C(O)NH₂, CF₃ or CH₃. J₂₉, J₃₀, J₃₂, and J₃₃ may each independently be H, OCH₃, OH, Br, Cl, F, I, C(O)NH₂, NH₂, or CH₃. J₃₄ may be CH, C, or N. J₃₄ may be C. J₃₄ may be CH or C. J₃₄ may be C or N. J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ may each independently be H, OCH₃, OH, Br, Cl, F, I, C(O)NH₂, CF₃,

NH₂, or CH₃. J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ may each independently be H, Cl or CH₃. J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ may each independently be H, OCH₃, OH, Br, Cl, F, NH₂ or CH₃. J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ may each be H, Cl or CH₃. J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ may each independently be H. J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ may each independently be Cl. J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ may each independently be CH₃. J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ may each independently be CF₃. J₄₀ may be CH, C, or N. J₄₀ may be C. J₄₀ may be CH or C. J₄₀ may be C or N. J₄₁ may be H, OH, Br, Cl, F, I, NH₂, CH₃ or

J₄₁ may be H. J₄₁ may be H, OH, Br, Cl, F, NH₂ or CH₃. J₄₂, J₄₃, J₄₄, J₄₅, and J₄₆ may each independently be H, OH, Br, Cl, F, I, NH₂ or CH₃. J₄₂, J₄₃, J₄₄, J₄₅, and J₄₆ may each independently be H. J₄₂, J₄₃, J₄₄, J₄₅, and J₄₆ may each independently be H, OH, NH₂, or CH₃. J₄₂, J₄₃, J₄₄, J₄₅, and J₄₆ may each independently be H, OH, Br, Cl, NH₂ or CH₃. J₄₇ may be CH, C or N. J₄₇ may be C. J₄₇ may be CH, C or N. J₄₇ may be CH or C. J₄₇ may be C or N. J₄₈ may be S, CH₂, C═O, O, or NH. J₄₈ may be S, CH₂ or NH. J₄₈ may be S. J₄₈ may be CH₂. J₄₈ may be NH. J₄₉ may be CH₂, C═O, S, O, or NH. J₄₉ may be CH₂ or C═O. J₄₉ may be S, O, or NH. J₄₉ may be CH₂, C═O or NH. J₄₉ may be CH₂, C═O or S. J₄₉ may be CH₂, C═O or O. J₅₅ may be C, or N. J₅₅ may be C. J₅₅ may be N. J₅₀, J₅₁, J₅₂, J₅₃, and _(J54,) may each independently be H, OH, NH₂, Br, Cl, F, I,

OCH₃, CF₃, CH₃ or may be absent when J₅₀, J₅₁, J₅₂, J₅₃, or J₅₄ is N. J₅₀, J₅₁, J₅₂, J₅₃, and J₅₄, may each independently be H, OH, Br, F, CH₃ or may be absent when J₅₀, J₅₁, J₅₂, J₅₃, or J₅₄ is N. J₅₀, J₅₁, J₅₂, J₅₃, and J₅₄, may each be H or may be absent when J₅₀, J₅₁, J₅₂, J₅₃, or J₅₄ is N. J₅₀, J₅₁, J₅₂, J₅₃, and J₅₄, may each be OH or may be absent when J₅₀, J₅₁, J₅₂, J₅₃, or J₅₄ is N. J₅₀, J₅₁, J₅₂, J₅₃, and J₅₄, may each be Br or may be absent when J₅₀, J₅₁, J₅₂, J₅₃, or J₅₄ is N. J₅₀, J₅₁, J₅₂, J ₅₃, and J₅₄, may each be F or may be absent when J₅₀, J₅₁, J₅₂, J ₅₃, or J₅₄ is N. J₅₀, J₅₁, J₅₂, J₅₃, and J₅₄, may each be CH₃ or may be absent when J₅₀, J₅₁, J₅₂, J₅₃, or J₅₄ is N. J₅₆ may be CH, C or N. J₅₆ may be C. J₅₆ may be CH or C. J₅₆ may be C or N. J₅₇ may be N or CH. J₅₇ may be CH. J₅₇ may be N. J₅₈, J₅₉, J₆₀, J₆₁, and J₆₂, may each independently be H, OH, NH₂, Br, Cl, F, I,

OCH₃, CF₃, or CH₃. J₅₈, J₅₉, J₆₀, J₆₁, and J₆₂, may each independently be H, F or CF₃. J₅₈, J₅₉, J₆₀, J₆₁, and J₆₂, may each independently be H, OH, NH₂, Br, Cl, F, I, OCH₃ or CH₃. J₆₃, J₆₄, J₆₅, J₆₆, and J₆₇, may each independently be H, OH, NH₂, Br, Cl, F, I,

OCH₃, CF₃, or CH₃. J₆₃, J₆₄, J₆₅, J₆₆, and J₆₇, may each independently be H, F or CF₃. J₆₃, J₆₄, J₆₅, J₆₆, and J₆₇, may each independently be H, OH, NH₂, Br, Cl, F, OCH₃ or CH₃. J₆₃ may be CH, C, or N. J₆₃ may be C or N. J₆₃ may be C. J₆₃ may be N. J₆₄ may be CH, CH₂, NH, CN═O, C═O, O, NCH₃, NC(O)OCH₃,

or N. J₆₄ may be CH, CH₂, NH, CN═O, C═O, O, CCH₃, NCH₃, NC(O)OCH₃,

or N. J₆₄ may be CH, CH₂, NH, CN═O, C═O, O, NCH₃, NC(O)OCH₃,

or N. J₆₅ may be CH₂, NH, C═O, O, S, NN═O, NCH₃, NC(O)OCH₃,

J₆₅ may be CH₂, NH, C═O, O, NN═O, NCH₃, NC(O)OCH₃,

J₆₆, J₆₇, J₆₈, and J₆₉ may each independently be H, OCH₃, OH, Br, Cl, F, I, C(O)NH₂, CF₃,

NH₂, or CH₃. J₆₆, J₆₇, J₆₈, and J₆₉ may each independently be H, OCH₃, Br or CF₃. J₆₆, J₆₇, J₆₈, and J₆₉ may each independently be H, OCH₃, OH, Br, Cl, F, C(O)NH₂, NH₂ or CH₃. J₇₀ may be C. J₇₀ may be CH or C. J₇₀ may be C or N. J₇₀ may be CH, C, or N. J₇₁, J₇₂, J₇₃, and J₇₄ may each independently be H, OCH₃, OH, Br, Cl, F, I, C(O)NH₂, CF₃,

NH₂, or CH₃. J₇₁, J₇₂, J₇₃, and J₇₄ may each independently be H, Br, CF₃, or CH₃. J₇₁, J₇₂, J₇₃, and J₇₄ may be H. J₇₁, J₇₂, J₇₃, and J₇₄ may be Br. J₇₁, J₇₂, J₇₃, and J₇₄ may be CF₃. J₇₁, J₇₂, J₇₃, and J₇₄ may be CH₃. J₇₅ may be CH, or N. J₇₅ may be CH. J₇₇ may be

J₇₇ may be

One or more of D₁-D₃ links to at least one ring in addition to the bicyclic structure of Formula I.

In accordance with a further aspect of the invention, there is provided a compound having the structure of Formula I as described herein, but provided that the compound is not one of the compounds in TABLE 1.

TABLE 1 Known AR BF3 Interactors. Internal External Number Identifier STRUCTURE 13312 ZINC 00298052

13309 ZINC 01234071

13310 ZINC 00297221

13232 ZINC 02992016

13050 ZINC 03365783

13300 ZINC 00270867

13299 ZINC 00499454

13304 ZINC 00270887

13258 ZINC 18191564

9125 ZINC 30469682

13186 ZINC 00513042

13224 ZINC 04106386

13250 ZINC 03149578

13303 ZINC 00270884

13257 ZINC 12345945

13243 ZINC 00253227

13424 ZINC 12346351

6054 ZINC 08718421

13029 ZINC 00210926

9128 ZINC 47424036

13216 ZINC 06025409

13260 ZINC 49491101

13416 ZINC 01869964

13411 ZINC 04106386

13214 ZINC 26472877

13235 ZINC 01037115

13127 ZINC 00392643

13261 ZINC 48546225

13215 ZINC 05504717

13167 NSC 105329

13206 ZINC 04962047

13145 ZINC 34603778

13245 ZINC 00555700

13036 ZINC 14961821

13166 ZINC 01723993

13164-B ZINC 02046058

13254 ZINC 18191551

13410 ZINC 04106383

13423 ZINC 18191568

13222 ZINC 02718340

13247 ZINC 48090221

13412 ZINC 02718340

13434 ZINC 00069102

13164-A ZINC 02046058

13220 ZINC 48544111

13225 ZINC 18191568

13436 ZINC 00068959

13255 ZINC 18191553

13163-A ZINC 02043019

13163-B ZINC 02043019

13256 ZINC 05848672

13427 ZINC 00588219

13259 ZINC 18191559

13226 ZINC 18191571

13562 Known see U.S. Pat. No. 6,207,679

13566 Known see U.S. Pat. No. 6,207,679

The compound may be selected from one or more of the active synthetic derivatives set out in TABLE 2.

TABLE 2 List of Active Synthetic AR BF3 Interactor Derivatives Internal Number STRUCTURE 9040

13551

9026

13561

9027

13559

13542

13508

13503

9037

13516

13522

13525

13511

13509

13540

13536

13504

13558

13500

13534

13554

13521

13567

13570

13571

13574

13577

13580

13585

13589

13592

13594

13597

13601

13603

13607

13611

13613

13618

13621

13624

13626

13628

13630

13634

13640

13642

13644

13646

13651

13653

13655

13658

13665

13677

13681

13683

13688

13692

13694

13696

13698

13702

13708

13713

13718

13730

13732

13736

13741

13743

13745

13752

13754

13759

13761

13764

13770

13772

13774

13776

13785

13787

9034

13550

13544

9028

13538

13512

13524

13530

13502

13543

13505

13548

13532

9043

13510

13560

13556

13549

13535

13552

13537

13541

13506

13568

13569

13573

13576

13579

13582

13587

13591

13593

13595

13600

13602

13606

13610

13612

13614

13619

13622

13625

13627

13629

13633

13639

13641

13643

13645

13650

13652

13654

13656

13660

13674

13680

13682

13684

13691

13693

13695

13697

13699

13704

13710

13717

13719

13731

13733

13738

13742

13744

13749

13753

13755

13760

13762

13766

13771

13773

13775

13782

13786

Alternatively, the compound may be selected from one or more of the following:

The compound may have the structure of Formula II:

wherein,

L₁ may be H, Cl, F, Br, OH, CF₃, NH₂, OCH₃, or CH₃;

L₂ may be H, Cl, F, Br, OH, NH₂, OCH₃, or CH₃;

L₃ may be H, Cl, F, Br, OH, NH₂, OCH₃, or CH₃;

L₄ may be H, Cl, F, Br, OH, NH₂, C(O)NHCH₃, CH₂OH, OCH₃, CF₃, CH₃,

L₅ may be H, OH, NH₂, OCH₃, CH₂CH₃, or CH₃;

L₆ may be H, OH, NH₂, OCH₃, CH₂CH₃, or CH₃;

L₇ may be H, F, Cl or Br;

L₈ may be H, Cl, F, Br, OH, NH₂, OCH₃, or CH₃;

L₉ may be H, Cl, F, Br, OH, NH₂, OCH₃, or CH₃; and

L₁₀ may be H, Cl, F, Br, OH, NH₂, I, CN, CH₂CH₃, CF₃, OCH₃,

or CH₃, provided that the compound is not one of the following:

The compound may be:

The compound may be:

The compound may have the structure of Formula III:

wherein,

R₁ is CH₃, OH, OCH₃, CH₂CH₃, or OCH₂CH₃;

R₂ is CH₃, OH, OCH₃, CH₂CH₃, or OCH₂CH₃;

or R₁ and R₂ form

M₁ is C or N;

M₂ is C or N;

Q₁ is H;

Q₂ is NH₂, Br, Cl, H, OCH₃, CH₂OH, OCH₂-Ph,

OH, F, I, C(O)NH₂,

NH₂, or CH₃;

Q₃ is NH₂, Br, Cl, H, OCH₃, CH₂OH, OCH₂-Ph,

OH, F, I, C(O)NH₂,

NH₂, or CH₃;

Q₄ is NH₂, Br, Cl, H, OCH₃, CH₂OH, OCH₂-Ph,

OH, F, I, C(O)NH₂,

NH₂, or CH₃; and

Q₅ is H, CH₃, CH₂CH₂OH,

OH, F, Br, Cl, I, or

The compound may be selected from one or more of the following:

The compound may be

or

The compound may be for use in the treatment of at least one indication selected from the group including: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, and age-related macular degeneration.

The modulating AR activity is for the treatment of at least one indication selected from the group including: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, and age-related macular degeneration.

The modulating AR activity may be for the treatment of prostate cancer. The mammalian cell may be a human cell. The cell may be a prostate cell. The cell may be a prostate cancer cell.

The compound may be for use in the treatment of at least one indication selected from the group consisting of: cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, and age related macular degeneration. The cancer may be AR-mediated cancer. The cancer may be selected from the group including of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer and bladder cancer. The cancer may be Taxene resistant triple negative breast cancer.

In accordance with a further aspect, there is provided a pharmaceutical composition for modulating AR activity, the composition including a compound described herein, and a pharmaceutically acceptable carrier.

In accordance with a further aspect, there is provided a method of modulating AR activity, the method including (a) administering a compound described herein or a pharmaceutical composition described herein to a subject in need thereof.

In accordance with a further aspect, there is provided a method for modulating AR activity, the method including administering to a mammalian cell a compound or pharmaceutically acceptable salt thereof as described herein.

In accordance with a further aspect, there is provided a use of a compound described herein, for modulating AR activity.

In accordance with a further aspect, there is provided a use of a compound described herein, for the manufacture of a medicament for modulating AR activity.

In accordance with a further aspect, there is provided a pharmaceutical composition including a compound or pharmaceutically acceptable salt thereof described herein and a pharmaceutically acceptable excipient.

In accordance with a further aspect, there is provided a commercial package including (a) a compound described herein; and (b) instructions for the use thereof for modulating AR activity.

In accordance with a further aspect, there is provided a commercial package including (a) a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier; and (b) instructions for the use thereof for modulating AR activity.

DETAILED DESCRIPTION

The BF3 site is an attractive target for direct inhibition of the AR co-activation. In silico computational drug discovery methods were used to conduct a virtual screen of ˜4 million purchasable lead-like compounds from the ZINC database (Irwin, J. et al. Abstracts of Papers Am. Chem. Soc. (2005) 230:U1009) to identify potential BF3 binders. The in silico methods included large-scale docking, in-site rescoring and consensus voting procedures.

It will be understood by a person of skill that COOH and NR₂ may include the corresponding ions, for example carboxylate ions and ammonium ions, respectively. Alternatively, where the ions are shown, a person of skill in the art will appreciate that the counter ion may also be present.

Those skilled in the art will appreciate that the point of covalent attachment of the moiety to the compounds as described herein may be, for example, and without limitation, cleaved under specified conditions. Specified conditions may include, for example, and without limitation, in vivo enzymatic or non-enzymatic means. Cleavage of the moiety may occur, for example, and without limitation, spontaneously, or it may be catalyzed, induced by another agent, or a change in a physical parameter or environmental parameter, for example, an enzyme, light, acid, temperature or pH. The moiety may be, for example, and without limitation, a protecting group that acts to mask a functional group, a group that acts as a substrate for one or more active or passive transport mechanisms, or a group that acts to impart or enhance a property of the compound, for example, solubility, bioavailability or localization.

In some embodiments, compounds of Formula I or Formula II above may be used for systemic treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty and age-related macular degeneration. In some embodiments compounds of Formula I or Formula II may be used in the preparation of a medicament or a composition for systemic treatment of an indication described herein. In some embodiments, methods of systemically treating any of the indications described herein are also provided.

Compounds as described herein may be in the free form or in the form of a salt thereof. In some embodiment, compounds as described herein may be in the form of a pharmaceutically acceptable salt, which are known in the art (Berge S. M. et al., J. Pharm. Sci. (1977) 66(1):1-19). Pharmaceutically acceptable salt as used herein includes, for example, salts that have the desired pharmacological activity of the parent compound (salts which retain the biological effectiveness and/or properties of the parent compound and which are not biologically and/or otherwise undesirable). Compounds as described herein having one or more functional groups capable of forming a salt may be, for example, formed as a pharmaceutically acceptable salt. Compounds containing one or more basic functional groups may be capable of forming a pharmaceutically acceptable salt with, for example, a pharmaceutically acceptable organic or inorganic acid. Pharmaceutically acceptable salts may be derived from, for example, and without limitation, acetic acid, adipic acid, alginic acid, aspartic acid, ascorbic acid, benzoic acid, benzenesulfonic acid, butyric acid, cinnamic acid, citric acid, camphoric acid, camphorsulfonic acid, cyclopentanepropionic acid, diethylacetic acid, digluconic acid, dodecylsulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, glucoheptanoic acid, gluconic acid, glycerophosphoric acid, glycolic acid, hemisulfonic acid, heptanoic acid, hexanoic acid, hydrochloric acid, hydrobromic acid, hydriodic acid, 2-hydroxyethanesulfonic acid, isonicotinic acid, lactic acid, malic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-napthalenesulfonic acid, naphthalenedisulphonic acid, p-toluenesulfonic acid, nicotinic acid, nitric acid, oxalic acid, pamoic acid, pectinic acid, 3-phenylpropionic acid, phosphoric acid, picric acid, pimelic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, succinic acid, sulfuric acid, sulfamic acid, tartaric acid, thiocyanic acid or undecanoic acid. Compounds containing one or more acidic functional groups may be capable of forming pharmaceutically acceptable salts with a pharmaceutically acceptable base, for example, and without limitation, inorganic bases based on alkaline metals or alkaline earth metals or organic bases such as primary amine compounds, secondary amine compounds, tertiary amine compounds, quaternary amine compounds, substituted amines, naturally occurring substituted amines, cyclic amines or basic ion-exchange resins. Pharmaceutically acceptable salts may be derived from, for example, and without limitation, a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation such as ammonium, sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese or aluminum, ammonia, benzathine, meglumine, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, glucamine, methylglucamine, theobromine, purines, piperazine, piperidine, procaine, N-ethylpiperidine, theobromine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N,N-dimethylaniline, N-methylpiperidine, morpholine, N-methylmorpholine, N-ethylmorpholine, dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, N,N′-dibenzylethylenediamine or polyamine resins. In some embodiments, compounds as described herein may contain both acidic and basic groups and may be in the form of inner salts or zwitterions, for example, and without limitation, betaines. Salts as described herein may be prepared by conventional processes known to a person skilled in the art, for example, and without limitation, by reacting the free form with an organic acid or inorganic acid or base, or by anion exchange or cation exchange from other salts. Those skilled in the art will appreciate that preparation of salts may occur in situ during isolation and purification of the compounds or preparation of salts may occur by separately reacting an isolated and purified compound.

In some embodiments, compounds and all different forms thereof (e.g. free forms, salts, polymorphs, isomeric forms) as described herein may be in the solvent addition form, for example, solvates. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent in physical association the compound or salt thereof. The solvent may be, for example, and without limitation, a pharmaceutically acceptable solvent. For example, hydrates are formed when the solvent is water or alcoholates are formed when the solvent is an alcohol.

In some embodiments, compounds and all different forms thereof (e.g. free forms, salts, solvates, isomeric forms) as described herein may include crystalline and amorphous forms, for example, polymorphs, pseudopolymorphs, conformational polymorphs, amorphous forms, or a combination thereof. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and/or solubility. Those skilled in the art will appreciate that various factors including recrystallization solvent, rate of crystallization and storage temperature may cause a single crystal form to dominate.

In some embodiments, compounds and all different forms thereof (e.g. free forms, salts, solvates, polymorphs) as described herein include isomers such as geometrical isomers, optical isomers based on asymmetric carbon, stereoisomers, tautomers, individual enantiomers, individual diastereomers, racemates, diastereomeric mixtures and combinations thereof, and are not limited by the description of the formula illustrated for the sake of convenience.

In some embodiments, pharmaceutical compositions as described herein may comprise a salt of such a compound, preferably a pharmaceutically or physiologically acceptable salt. Pharmaceutical preparations will typically comprise one or more carriers, excipients or diluents acceptable for the mode of administration of the preparation, be it by injection, inhalation, topical administration, lavage, or other modes suitable for the selected treatment. Suitable carriers, excipients or diluents (used interchangeably herein) are those known in the art for use in such modes of administration.

Suitable pharmaceutical compositions may be formulated by means known in the art and their mode of administration and dose determined by the skilled practitioner. For parenteral administration, a compound may be dissolved in sterile water or saline or a pharmaceutically acceptable vehicle used for administration of non-water soluble compounds such as those used for vitamin K. For enteral administration, the compound may be administered in a tablet, capsule or dissolved in liquid form. The tablet or capsule may be enteric coated, or in a formulation for sustained release. Many suitable formulations are known, including, polymeric or protein microparticles encapsulating a compound to be released, ointments, pastes, gels, hydrogels, or solutions which can be used topically or locally to administer a compound. A sustained release patch or implant may be employed to provide release over a prolonged period of time. Many techniques known to one of skill in the art are described in Remington: the Science & Practice of Pharmacy by Alfonso Gennaro, 20^(th) ed., Lippencott Williams & Wilkins, (2000). Formulations for parenteral administration may, for example, contain excipients, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated naphthalenes. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds. Other potentially useful parenteral delivery systems for modulatory compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.

Compounds or pharmaceutical compositions as described herein or for use as described herein may be administered by means of a medical device or appliance such as an implant, graft, prosthesis, stent, etc. Also, implants may be devised which are intended to contain and release such compounds or compositions. An example would be an implant made of a polymeric material adapted to release the compound over a period of time.

An “effective amount” of a pharmaceutical composition as described herein includes a therapeutically effective amount or a prophylactically effective amount. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as reduced tumor size, increased life span or increased life expectancy. A therapeutically effective amount of a compound may vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as smaller tumors, increased life span, increased life expectancy or prevention of the progression of prostate cancer to an androgen-independent form. Typically, a prophylactic dose is used in subjects prior to or at an earlier stage of disease, so that a prophylactically effective amount may be less than a therapeutically effective amount.

It is to be noted that dosage values may vary with the severity of the condition to be alleviated. For any particular subject, specific dosage regimens may be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Dosage ranges set forth herein are exemplary only and do not limit the dosage ranges that may be selected by medical practitioners. The amount of active compound(s) in the composition may vary according to factors such as the disease state, age, sex, and weight of the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It may be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.

In some embodiments, compounds and all different forms thereof as described herein may be used, for example, and without limitation, in combination with other treatment methods for at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty and age-related macular degeneration. For example, compounds and all their different forms as described herein may be used as neoadjuvant (prior), adjunctive (during), and/or adjuvant (after) therapy with surgery, radiation (brachytherapy or external beam), or other therapies (eg. HIFU).

In general, compounds as described herein should be used without causing substantial toxicity. Toxicity of the compounds as described herein can be determined using standard techniques, for example, by testing in cell cultures or experimental animals and determining the therapeutic index, i.e., the ratio between the LD50 (the dose lethal to 50% of the population) and the LD100 (the dose lethal to 100% of the population). In some circumstances however, such as in severe disease conditions, it may be appropriate to administer substantial excesses of the compositions. Some compounds as described herein may be toxic at some concentrations. Titration studies may be used to determine toxic and non-toxic concentrations. Toxicity may be evaluated by examining a particular compound's or composition's specificity across cell lines using PC3 cells as a negative control that do not express AR. Animal studies may be used to provide an indication if the compound has any effects on other tissues. Systemic therapy that targets the AR will not likely cause major problems to other tissues since anti-androgens and androgen insensitivity syndrome are not fatal.

Compounds as described herein may be administered to a subject. As used herein, a “subject” may be a human, non-human primate, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc. The subject may be suspected of having or at risk for having a cancer, such as prostate cancer, breast cancer, ovarian cancer or endometrial cancer, or suspected of having or at risk for having acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, or age-related macular degeneration. Diagnostic methods for various cancers, such as prostate cancer, breast cancer, ovarian cancer or endometrial cancer, and diagnostic methods for acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, or age-related macular degeneration and the clinical delineation of cancer, such as prostate cancer, breast cancer, ovarian cancer or endometrial cancer, diagnoses and the clinical delineation of acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, or age-related macular degeneration are known to those of ordinary skill in the art.

Definitions used include ligand-dependent activation of the androgen receptor (AR) by androgens such as dihydrotestosterone (DHT) or the synthetic androgen (R1881) used for research purposes. Ligand-independent activation of the AR refers to transactivation of the AR in the absence of androgen (ligand) by, for example, stimulation of the cAMP-dependent protein kinase (PKA) pathway with forskolin (FSK).

Some compounds and compositions as described herein may interfere with a mechanism specific to ligand-dependent activation (e.g., accessibility of the ligand binding domain (LBD) to androgen) or to ligand-independent activation of the AR.

Various alternative embodiments and examples of the invention are described herein. These embodiments and examples are illustrative and should not be construed as limiting the scope of the invention.

Materials and Methods In Silico Screening

Ten million commercially available compounds from the ZINC12.0 structural libraries (Irwin, J. J. and Shoichet, B. K. ZINC—a free database of commercially available compounds for virtual screening. J Chem Inf Model 2005, 45, 177-182) were imported into a molecular database using Molecular Operating Environment (MOE) version 2007.09 (MOE, Chemical Computing Group, Inc., 2008, www.chemcomp.com). These structures were energy minimized using an MMFF94x force field, exported in SD format and rigidly docked into the BF3 site of the protein structures 4HLW with Glide software (Friesner, R. A. et al. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem. 2004, 25, 739-49). About 2 million molecules that had a GlideScore←5.0 were then re-docked into the same BF3 binding cavity using the electronic high-throughput screening (eHiTS) docking module (Zsoldos, Z. et al. eHiTS: a new fast, exhaustive flexible ligand docking system. J Mol Graph Model 2007, 26, 198-212). From this, 500,000 structures with eHiTS docking scores <-3.0 threshold were identified. They were scored by the LigX™ module of the MOE to account for the receptor/ligand flexibility. The pKi binding affinity was scored after energy minimization to select the ligands that showed the best binding characteristics defined mainly by the energy of hydrogen bonds and hydrophobic interactions. The virtual hits were scored using Molecular Mechanics, the Generalized Born model and Solvent Accessibility (MM-GB/SA) method with OPLS 2005 and GB/SA in MacroModelTM to calculate the free energies of the optimal chemical poses (Maestro, Schrodinger, LLC, New York, N.Y., 2008. www.schrodinger.com). The root mean square deviation (RMSD) was calculated between the Glide poses and the eHiTS poses to evaluate the docking consistency and thus to establish the most probable binding pose for a given ligand. Finally, very large and very small molecules were penalized based on a heavy atom count.

With this information, a cumulative scoring of five different predicted parameters (RMSD, heavy atoms count, LigX, Macromodel, pKi) was generated where each molecule receive a binary 1.0 score for every ‘top 10% appearance’. The final cumulative vote (with the maximum possible value of 5) was then used to rank the training set entries. Based on the cumulative score 5000 compounds were selected and subjected to visual inspection. After this final selection step 200 compounds were selected out of which 150 chemical substances could be readily purchased in sufficient purity and quantity.

General Synthesis and Characterization of Compounds Exemplary Scheme 1: Synthesis of Compound 13163.

At 0° C., a solution of para-toluenesulfonic acid (13.4 g, 0.55 eq, 70.4 mmol) in acetonitrile (150 mL) was added drop-wise over 1 h to a solution of indole (15 g, 1.0 eq, 128.0 mmol) in acetonitrile (500 mL). The mixture was kept for additionnal 6 h at 0° C. The subsequent precipitate was filtered (at 0° C.) and washed with acetonitrile (three times). The precipitate was neutralized with saturated NaHCO₃ solution and extracted with AcOEt (3×100 mL). The organic extracts were combined, washed with brine, dried over Na₂SO₄; filtered and concentrated under reduced pressure. Any purification was needed and the crude was transformed in corresponding hydrochloride with HCl 2 M solution in ether and the precipitate salt was filtered to afford 14.8 g of the white solid (54.7 mmol, 85%).

Analysis

-   -   M.p.=169-170° C.     -   t_(R) (HPLC)=3.01 min     -   MS (ESI+) m/z=235.12 [(M+H)⁺]     -   HRMS (ESI+): calculated for C₁₆H₁₅N₂, m/z=235.1230; found,         235.1237; calculated for C₁₆H₁₄N₂Na, m/z=257.1049; found,         257.1058     -   ¹H NMR (400 MHz, DMSO-d₆): δ (ppm)=11.45 (s, 1H, H₁₂), 7.77 (d,         J=8.0 Hz, 1H, H₁₈), 7.68 (d, J=2.6 Hz, 1H, H₁₁), 7.58-7.50 (m,         1H, H₆), 7.45 (d, J=8.4 Hz, 1H, H₁₅), 7.43-7.38 (m, 4H,         H_(1, 2)), 7.35-7.33 (m, 1H, H₃), 7.17 (ddd, J=8.2, 7.1, 1.1 Hz,         1H, H₁₆), 7.07 (ddd, J=8.0, 7.1, 1.0 Hz, 1H, H₁₇), 5.58 (t,         J=8.7 Hz, 1H, H₁₈), 3.67 (d, J=8.7 Hz, 2H, H₉).     -   ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm)=137.96 (C₄-arom.), 137.00         (C₁₃-arom.), 135.72 (C₅-arom.), 128.74 (C₁H-arom.), 128.50         (C₂H-arom.), 126.36 (C₁₄-arom.), 126.11 (C₆H-arom.), 125.72         (C₁₁H-arom.), 122.31 (C₁₆H-arom.), 119.69 (C₁₇H-arom.), 119.48         (C₁₈H-arom.), 119.38 (C₃H-arom.), 112.30 (C₁₅H-arom.), 110.24         (C₁₀-arom.), 56.55 (C₈H), 35.37 (C₉H₂).

General Synthesis Methods

¹H and ¹³C NMR spectra (COSY, ¹H/¹³C 2D-correlations) were recorded with Bruker

Avance III™ 400 MHz. Processing of the spectra was performed with MestRec™ software and data are reported as follows: chemical shifts (δ) in parts per million, coupling constants (J) in hertz (Hz). The high-resolution mass spectra were recorded in positive ion-mode with an ESI ion source on an Agilent™ Time-of-Flight LC/MS mass spectrometer. HPLC analyses and purity of >95% were performed by analytical reverse-phase HPLC with a Agilent™ instrument with variable detector using column Agilent Zorbax 4.6×5 mm, 5 um; flow: 2.0 mL·min⁻¹, H₂O (0.1% FA)/CH₃CN (0.1% FA), gradient 2→98% (6 min) and 98% (0.3 min). Melting points were determined with a Fischer-Jonhs.

Analytical Methods:

¹H and ¹³C NMR spectra (COSY, ¹H/¹³C 2D-correlations) were recorded with Bruker Avance III™ 400 MHz. Processing of the spectra was performed with MestRec™ software and data are reported as follows: chemical shifts (δ) in parts per million, coupling constants (J) in hertz (Hz). The high-resolution mass spectra were recorded in positive ion-mode with an ESI ion source on an Agilent™ Time-of-Flight LC/MS mass spectrometer. HPLC analyses and purity of >95% were performed by analytical reverse-phase HPLC with a Agilent™ instrument with variable detector using column Agilent Zorbax 4.6×5 mm, 5 um; flow: 2.0 mL·min⁻¹, H₂O (0.1% FA)/CH₃CN (0.1% FA), gradient 2→98% (6 min) and 98% (0.3 min).

Dimethyl- & Cyclohexyl-Hydroindole Moiety

General Procedure 1

Phenylhydrazine (1.0 eq) aldehyde (isobutyraldehyde or cyclohexanecarboxaldehyde) (1.0 eq) were diluted in AcOH (0.1 M). The mixture was heated at 65° C. for 2 h (until complete conversion). Reaction mixture containing imine intermediate was allowed to reach r.t. and indole (1.0 eq) was added to the mixture which was stirred additional 2 h at r.t. (until complete conversion). Acetic acid was removed under vacuo. Then, the residue was poured with H₂O and neutralized at pH 7 with sat. NaHCO₃ solution. The aqueous layer was extracted with AcOEt (×3) and organic layers were combined, washed with brine, dried over Na₂SO₄ and evaporated under reduced pressure. Then, crude was purified by automated combi-flash to afford the good compound.

General Procedure 2

Benzyloxy compound (1.0 eq) was dissolved in mixture of MeOH (0.05 M) and the system was purged with vacuum/N₂ (×3). Then, Pd/C (20% w/w) was added to the mixture and purged again with vacuum/H₂ and put under H₂ atmosphere. The reaction was stirred overnight at r.t. under H₂ atmosphere. The reaction mixture was filtered on a plug of Celite which was washed with MeOH. The filtrate was concentrated under reduced pressure and the residue was purified by combi-flash to afford the good compound.

General Procedure 3

Imine compound (1.0 eq) was dissolved in AcOH (0.1 M) and the system was put under argon atmosphere. Then, NaBH₃CN (1.1 eq) was added quickly. Then, the reaction was stirred at r.t. After overnight, the reaction mixture was concentrated and the crude was quenched with H₂O. Aqueous layer was neutralized with saturated NaHCO₃ solution until pH 7 and extracted with AcOEt (×2). The combined organic layers were washed with brine, dried over Na₂SO₄ and rotary evaporated. The crude was purified by automated combi-flash to afford the good compound.

General Procedure 4

From ester compound (1.0 eq) was diluted in mixture of MeOH/Acetone (1:3, 0.1 M). The mixture was stirred and a solution of LiOH (2.0 eq) in H₂O (0.85 M) was added drop-wise over 5 min. Then, the mixture was stirred overnight at r.t. The reaction mixture was diluted in a mixture of Et₂O and H₂O and the aqueous phase was washed and then acidified with concentrated HCl solution until pH 3. The aqueous layer was extracted with Et₂O (×2). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give pure product.

General Procedure 5

A dried vessel was charged with LiAlH₄ (4.0 eq), enclosed with condenser and rubber cap and put under argon atmosphere. Then, carboxylic acid (1.0 eq) was dissolved in anhydrous THF (0.28 M) and was added in system which was stirred 2 h at 70° C. The excess of LiAlH₄ was destroyed by adding AcOEt drop-wise (exothermic reaction) and then by adding H₂O. Aqueous saturated NH₄Cl solution was added and the whole was extracted with AcOEt (×2). The combined organic layers were washed with H₂O and brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude was purified by automated combi-flash to afford the good compound.

General Procedure 6

Phenylhydrazine (1.0 eq) and isobutyraldehyde (1.0 eq) were diluted in AcOH (0.1 M). The mixture was heated at 65° C. for 2 h (until complete conversion). Reaction mixture containing imine intermediate was allowed to reach r.t. Acetic acid was removed under vacuo. The residue was poured with H₂O and neutralized at pH 7 with sat. NaHCO₃ solution. The aqueous layer was extracted with AcOEt (×3) and organic layers were combined, washed with brine, dried over Na₂SO₄ and evaporated under reduced pressure. Then, residue corresponding to imine intermediate was diluted in ACN (0.5 M). Azaindole (0.9 eq) and ZnCl₂ (0.9 eq) were introduced in microwave vessel. The mixture was stirred and heated by microwave 3 h at 120° C. The resulting crystals (after avernight at r.t.) was filtered and washed with 1 N aqueous NaOH solution (50 mL) and extracted with AcOEt (×2). The organic layers were combined, washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure to provide pure compound.

Dimethyl-Hydroindole Moiety

3-(3,3-dimethylindolin-2-yl)-5-methyl-1H-indole (Procedure 1)

VPC Number LabBook Code ✓ IC₅₀ (eGFP) = 1.5 13 535 CA 2-36 F9-15 (yield = 63%) ✓ IC₅₀ (PSA) = 1.87

✓ t_(R) (HPLC) = 4.07 min ✓ MS (ESI+) m/z = 277.1719 [(M + H)⁺] ✓ HRMS (ESI+): calculated for C₁₉H₂₁N₂O, m/z = 277.1699; found, 277.1708 ✓ ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 10.83 (s, 1H, H₁₄), 7.33 (d, J = 0.6 Hz, 1H, H₂₀₎, 7.26 (d, J = 2.0 Hz, H₁₃), 7.25 (d, J = 8.0 Hz, 1H, H₁₇), 7.01 (d, J = 7.2 Hz, 1H, H₆), 6.97 (td, J = 7.6, 1.3 Hz, 1H, H₂), 6.88 (dd, J = 8.3, 1.5 Hz, 1H, H₁₈), 6.60 (td, J = 7.6, 1.2 Hz, 1H, H₁), 6.59 (d, J = 7.6 Hz, 1H, H₃), 5.82 (d, J = 2.4 Hz, 1H, H₇), 4.76 (d, J = 2.2 Hz, 1H, H₈), 2.33 (s, 3H, H₂₁), 1.39 (s, 3H, H₁₀), 0.74 (s, 3H, H₁₁). ✓ ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 150.99 (C₄-arom.), 138.68 (C₅- arom.), 135.33 (C₁₅-arom.), 127.54 (C₁₉-arom.), 127.29 (C₂H-arom.), 127.01 (C₁₆- arom.), 124.09 (C₁₃H-arom.), 122.80 (C₁₈H-arom.), 122.45 (C₆H-arom.), 119.77 (C₂₀H-arom.), 117.53 (C₁H-arom.), 113.64 (C₁₂-arom.), 111.60 (C₁₇H-arom.), 108.85 (C₃H-arom.), 68.17 (C₈H), 45.20 (C₉), 27.15 (C₁₀H₃), 25.01 (C₁₁H₃), 21.87 (C₂₁H₃).

3-(3,3-dimethylindolin-2-yl)-5-methoxy-1H-indole (Procedure 1)

VPC Number LabBook Code ✓ IC₅₀ (eGFP) = 2.2 13 536 CA 2-38 F10-19 (yield = 46%) ✓ IC₅₀ (PSA) = 2.52

✓ t_(R) (HPLC) = 3.82 min ✓ MS (ESI+) m/z = 293.1668 [(M + H)⁺] ✓ HRMS (ESI+): calculated for C₁₉H₂₁N₂O, m/z = 293.1648; found, 293.1654 ✓ ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 10.79 (s, 1H, H₁₄), 7.27 (d, J = 2.5 Hz, 1H, H₁₃), 7.24 (d, J = 8.8 Hz, 1H, H₁₇), 7.02 (br d, J = 7.2 Hz, 1H, H₆), 6.97 (td, J = 7.6, 1.3 Hz, 1H, H₂), 6.88 (d, J = 2.4 Hz, 1H, H₂₀), 6.70 (dd, J = 8.8, 2.4 Hz, 1H, H₁₈), 6.61 (td, J = 7.6, 1.2 Hz, 1H, H₁), 6.59 (d, J = 7.6 Hz, 1H, H₃), 5.82 (d, J = 2.0 Hz, 1H, H₇), 4.73 (d, J = 1.9 Hz, 1H, H₈), 3.62 (s, 3H, H₂₂), 1.38 (s, 3H, H₁₀), 0.78 (s, 3H, H₁₁). ✓ ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 153.22 (C₁₉-arom.), 151.10 (C₄- arom.), 138.59 (C₅-arom.), 132.18 (C₁₅-arom.), 127.37 (C₂H-arom.), 127.36 (C₁₆-arom.), 124.83 (C₁₃H-arom.), 122.32 (C₆H-arom.), 117.51 (C₁H-arom.), 114.38 (C₁₂-arom.), 112.44 (C₁₇H-arom.), 111.21 (C₁₈-arom.), 108.72 (C₃H-arom.), 102.31 (C₂₀H-arom.), 68.27 (C₈H), 55.63 (C₂₂H₃), 45.21 (C₉), 27.73 (C₁₀H₃) 24.58 (C₁₁H₃).

3-(3,3-dimethylindolin-2-yl)-5-amine-1H-indole (Procedure 1)

VPC Number LabBook Code ✓ IC₅₀ (eGFP) = 7.7 13 538 CA 2-47 F7-17 (yield = 45%) ✓ IC₅₀ (PSA) = No Data

✓ t_(R) (HPLC) = 2.56 min ✓ MS (ESI+) m/z = 278.1668 [(M + H)⁺] ✓ HRMS (ESI+): calculated for C₁₈H₂₀N₃, m/z = 278.1652; found, 278.1657 ✓ ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 10.53 (d, J = 1.6 Hz, 1H, H₁₄), 7.14 (d, J = 2.4 Hz, 1H, H₁₃), 7.08 (d, J = 8.4 Hz, 1H, H₁₇), 7.00 (dd, J = 7.2, 0.7 Hz, 1H, H₆) 6.95 (td, J = 7.6, 1.3 Hz, 1H, H₂), 6.86 (d, J = 2.0 Hz, 1H, H₂₀), 6.60 (td, J = 7.6, 0.8 Hz, 1H, H₂,) 6.57 (d, J = 7.6 Hz, 1H, H₃), 6.51 (dd, J = 8.5, 2.0 Hz, 1H, H₁₈), 5.78 (s, 1H, H₇), 4.86 (s 2H, H₂₁), 4.69 (s, 1H, H₈), 1.39 (s, 3H, H₁₀), 0.75 (s, 3H, H₁₁). ✓ ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 150.97 (C₄-arom.), 138.81 (C₅-arom.), 140.00 (C₁₉-arom.), 131.08 (C₁₅-arom.), 128.25 (C₁₆-arom.), 127.21 (C₂H-arom.), 123.86 (C₁₃H-arom.), 122.47 (C₆H-arom.), 117.47 (C₁H-arom.), 112.50 (C₁₂-arom.), 112.36 (C₁₈H-arom.), 111.97 (C₁₇-arom.), 108.86 (C₃H-arom.), 104.09 (C₂₀H-arom.), 68.29 (C₈H), 45.21 (C₉), 27.00 (C₁₀H₃, 25.15 (C₁₁H₃).

3-(3,3-dimethylindolin-2-yl)-6-(benzyloxy)-1H-indole (Procedure 1)

VPC Number LabBook Code ✓ IC₅₀ (eGFP) = 11.4 13 544 CA 2-54 Precipitate (yield = 53%) ✓ IC₅₀ (PSA) = No Data

✓ t_(R) (HPLC) = 4.60 min ✓ MS (ESI+) m/z = 369.1981 [(M + H)⁺] ✓ HRMS (ESI+): calculated for C₂₅H₂₅N₂O, m/z = 369.1961; found, 369.1979 ✓ ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 10.77 (s, 1H, H₁₄), 7.47 (d, J = 7.1 Hz, 2H, H_(24, 28)), 7.42-7.38 (m, 3H, H_(20, 25, 27)), 7.35-7.31 (m, 1H, H₂₆) 7.18 (d, J = 2.1 Hz, 1H, H₁₃), 6.99 (d, J = 6.8 Hz, 1H, H₆), 6.98-6.94 (m, 2H, H₂, ₁₇), 6.69 (dd, J = 8.7, 2.3 Hz, 1H, H₁₉), 6.63-6.55 (m, 2H, H_(1, 3),), 5.83 (d, J = 2.3 Hz, 1H, H₇), 5.11 (s, 2H, H₂₂), 4.73 (d, J = 2.2 Hz, 1H, H₈), 1.37 (s, 3H, H₁₀), 0.73 (s, 3H, H₁₁). ✓ ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 154.69 (C₁₈-arom.), 150.96 (C₄-arom.), 138.64 (C₅-arom.), 138.14 (C₂₃-arom.), 137.52 (C₁₅-arom.), 128.84 (C_(25, 27)H-arom.), 128.08 (C₂₆H-arom.), 127.96 (C_(24, 28)H-arom.), 127.32 (C₂H-arom.), 122.77 (C₁₃H-arom.), 122.41 (C₆H-arom.), 121.88 (C₁₆-arom.), 120.79 (C₂₀H-arom.), 117.54 (C₁H-arom.), 114.22 (C₁₂-arom.), 109.60 (C₁₉H-arom.), 108.83 (C₃H-arom.), 96.33 (C₁₇H-arom.), 69.92 (C₂₂H₂), 68.20 (C₈H, 45.15 (C₉), 27.16 (C₁₀H₃), 24.91 (C₁₁H₃).

3-(3,3-dimethylindolin-2-yl)-7-(benzyloxy)-1H-indole (Procedure 1)

VPC Number LabBook Code ✓ IC₅₀ (eGFP) = 3.7 13 543 CA 2-55 F7-10 (yield = 61%) ✓ IC₅₀ (PSA) = 3.19

✓ t_(R) (HPLC) = 4.67 min ✓ MS (ESI+) m/z = 369.1976 [(M + H)⁺] ✓ HRMS (ESI+): calculated for C₂₅H₂₅N₂O, m/z = 369.1961; found, 369.1957 ✓ ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.10 (d, J = 1.6 Hz, 1H, H₁₄), 7.58 (d, J = 7.8 Hz, 2H, H_(24, 28)), 7.46-7.39 (m, 2H, H_(25, 27)), 7.38-7.31 (m, 1H, H₂₆) 7.22 (d, J = 2.4 Hz, 1H, H₁₃), 7.15 (d, J = 8.0 Hz, 1H, H₂₀), 7.00 (d, J = 7.0 Hz, 1H, H₆), 6.96 (td, J = 7.6, 1.3 Hz, 1H, H₂), 6.85 (t, J = 7.8 Hz, 1H, H₁₉), 6.73 (d, J = 7.6 Hz, 1H, H₁₈, 6.62-6.56 (m, 2H, H_(1, 3)), 5.85 (d, J = 2.4 Hz, 1H, H₇), 5.26 (s, 2H, H₂₂), 4.77 (d, J = 2.2 Hz, 1H, H₈), 1.38 (s, 3H, H₁₀), 0.74 (s, 3H, H₁₁). ✓ ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 150.95 (C₄-arom.), 145.54 (C₁₇-arom.), 138.61 (C₅-arom.), 137.89 (C₂₃-arom.), 128.97 (C₁₆-arom.), 128.83 (C_(25, 27)H-arom.), 128.17 (C₂₆H-arom.), 128.01 (C_(24, 28)H-arom.), 127.32 (C₂H-arom.), 127.15 (C₁₅-arom.), 123.71 (C₁₃H-arom.), 122.43 (C₆H-arom.), 119.23 (C₁₉H-arom.), 117.57 (C₁H-arom.), 114.81 (C₁₂-arom.), 113.19 (C₂₀H-arom.), 108.83 (C₃H-arom.), 103.08 (C₁₈H-arom.), 69.56 (C₂₂H₂), 68.03 (C₈H), 45.20 (C₉), 27.19 (C₁₀H₃), 24.89 (C₁₁H₃).

3-(3,3-dimethylindolin-2-yl)-6-hydroxy-1H-indole (Procedure 2)

VPC Number LabBook Code ✓ IC₅₀ (eGFP) = 5.7 13 542 CA 2-61 F3-8 (yield = 62%) ✓ IC₅₀ (PSA) = No Data

✓ t_(R) (HPLC) = 3.25 min ✓ MS (ESI+) m/z = 279.1485 [(M + H)⁺] ✓ HRMS (ESI+): calculated for C₁₈H₁₉N₂O, m/z = 279.1492; found, 279.1485 ✓ ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 10.55 (s, 1H, H₁₄), 8.84 (s, 1H, H₂₁), 7.28 (d, J = 8.5 Hz, 1H, H₂₀), 7.08 (d, J = 2.0 Hz, 1H, H₁₃), 6.99 (d, J = 6.8 Hz, 1H, H₆), 6.95 (td, J = 7.6, 1.3 Hz, 1H, H₂), 6.71 (d, J = 2.0 Hz, 1H,H₁₇), 6.62-6.54 (m, 2H, H_(1, 3)), 6.47 (dd, J = 8.6, 2.2 Hz, 1H, H₁₉), 5.79 (d, J = 2.4 Hz, 1H, H₇) 4.70 (d, J = 2,1 Hz, 1H, H₈), 1.37 (s, 3H, H₁₀), 0.73 (s, 3H, H₁₁). ✓ ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 153.20 (C₁₈-arom.), 150.98 (C₄-arom.), 138.70 (C₅-arom.), 138.04 (C₁₅-arom.), 127.28 (C₂H-arom.), 122.40 (C₆H-arom.), 121.88 (C₁₃H-arom.), 120.84 (C₁₆-arom.), 120.50 (C₂₀H-arom.), 117.48 (C₁H-arom.), 114.08 (C₁₂-arom.), 109.39 (C₁₉H-arom.), 108.78 (C₃H-arom.), 96.92 (C₁₇H-arom.), 68.27 (C₈H), 45.10 (C₉), 27.17 (C₁₀H₃), 24.90 (C₁₁H₃).

3-(3,3-dimethylindolin-2-yl)-7-hydroxy-1H-indole (Procedure 2)

VPC Number LabBook Code ✓ IC₅₀ (eGFP) = 0.5 13 541 CA 2-62 F6-11 (yield = 37%) ✓ IC₅₀ (PSA) = 0.94

✓ t_(R) (HPLC) = 3.51 min ✓ MS (ESI+) m/z = 279.1525 [(M + H)⁺] ✓ HRMS (ESI+): calculated for C₁₈H₁₉N₂O, m/z = 279.1492; found, 279.1496 ✓ ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 10.76 (s, 1H, H₁₄), 9.46 (s, 1H, H₂₁), 7.19 (d, J = 2.4 Hz, 1H, H₁₃), 7.02-6.98 (m, 2H, H_(6, 20)), 6.96 (td, J = 7.6, 1.3 Hz, 1H, H₂), 6.73 (t, J = 7.7 Hz, 1H, H₁₉), 6.62-6.55 (m, 2H, H_(1, 3)), 6.48 (dd, J = 7.5, 0.6 Hz, 1H, H₁₈), 5.82 (d, J = 2.4 Hz, 1H, H₇), 4.75 (d, J = 2.2 Hz, 1H, H₈), 1.38 (s, 3H, H₁₀), 0.74 (s, 3H, H₁₁). ✓ ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 150.98 (C₄-arom.), 143.94 (C₁₇-arom.), 138.67 (C₅-arom.), 129.24 (C₁₆-arom.), 127.29 (C₂H-arom.), 126.97 (C₁₃H-arom.), 123.40 (C₁₃H-arom.), 122.41 (C₆H-arom.), 119.42 (C₁₉H-arom.), 117.52 (C₁H-arom.), 114.60 (C₁₂-arom.), 111.24 (C₂₀H-arom.), 108.80 (C₃H-arom.), 105.55 (C₁₈H-arom.), 68.08 (C₈H), 45.16 (C₉), 27.17 (C₁₀H₃), 24.88 (C₁₁H₃).

3-(3,3-dimethylindolin-2-yl)-7-methyl-1H-indole (Procedure 1)

VPC Number LabBook Code ✓ IC₅₀ (eGFP) = No Data 13 546 CA 2-67 F4-10 (yield = 62%) ✓ IC₅₀ (PSA) = No Data

✓ t_(R) (HPLC) = 4.16 min ✓ MS (ESI+) m/z = 277.1705 [(M + H)⁺] ✓ HRMS (ESI+): calculated for C₁₉H₂₁N₂, m/z = 277.1699; found, 277.1707 ✓ ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 10.94 (s, 1H, H₁₄), 7.39-7.35 (m, 1H, H₂₀), 7.31 (d, J = 2.4 Hz, 1H, H₁₃), 7.01 (d, J = 7.2 Hz, 1H, H₆), 6.97 (td, J = 7.6, 1.3 Hz, 1H, H₂), 6.87-6.83 (m, 2H, H_(18, 19)), 6.61 (td, J = 7.2, 0.8 Hz, 1H, H₁), 6.58 (d, J = 7.6 Hz, 1H, H₃), 5.84 (d, J = 2.4 Hz, 1H, H₇), 4.80 (d, J = 2.2 Hz, 1H, H₈), 2.46 (s, 3H, H₂₁), 1.39 (s, 3H, H₁₀), 0.74 (s, 3H, H₁₁). ✓ ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 150.97 (C₄-arom.), 138.68 (C₅-arom.), 136.42 (C₁₅-arom.), 127.32 (C₂H-arom.), 126.97 (C₁₆-arom.), 123.73 (C₁₃H-arom.), 122.42 (C₆H-arom.), 121.72 (C₁₉H-arom.), 120.90 (C₁₇-arom.), 118.96 (C₁₈H-arom.), 117.73 (C₂₀H-arom.), 117.57 (C₁H-arom.), 114.63 (C₁₂-arom.), 108.85 (C₃H-arom.), 68.11 (C₈H), 45.17 (C₉), 27.16 (C₁₀H₃), 24.95 (C₁₁H₃), 17.27 (C₂₁H₃).

VPC Number LabBook Code ✓ IC₅₀ (eGFP) = No Data 13 555 CA 2-90 F4-7 (yield = 62%) ✓ IC₅₀ (PSA) = No Data

✓ t_(R) (HPLC) = 4.12 min ✓ MS (ESI+) m/z = 281.1456 [(M + H)⁺] ✓ HRMS (ESI+): calculated for C₁₈H₁₈FN₂, m/z = 281.1449; found, 281.1454 ✓ ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.49 (s, 1H, H₁₄), 7.41-7.34 (m, 2H, H_(13, 20)), 7.01 (d, J = 7.2 Hz, 1H, H₆), 6.97 (td, J = 7.6, 1.3 Hz, 1H, H₂), 6.94-6.86 (m, 2H, H_(18, 19)), 6.65-6.57 (m, 2H, H_(1, 3)), 5.91 (d, J = 2.5 Hz, 1H H₇), 4.79 (d, J = 2.2 Hz, 1H, H₈), 1.38 (s, 3H, H₁₀), 0.74 (s, 3H, H₁₁). ✓ ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 150.85 (C₄-arom.), 148.48 (C₁₇- arom.), 138.51 (C₅-arom.), 131.28 (d, J = 5.9 Hz, C₁₆-arom.), 127.39 (C₂H- arom.), 125.19 (d, J = 0.6 Hz, C₁₃H-arom.), 124.70 (d, J = 13.1 Hz, C₁₅- arom.), 122.45 (C₆H-arom.), 119.05 (d, J = 6.3 Hz, C₁₉H-arom.), 117.70 (C₁H- arom.), 116.45 (d, J = 3.2 Hz, C₂₀H-arom.), 115.49 (d, J = 1.9 Hz, C₁₂-arom.), 108.91 (C₃H-arom.), 106.02 (d, J = 15.9 Hz, C₁₈H-arom.), 67.86 (C₈H), 45.25 (C₉), 27.12 (C₁₀H₃), 24.90 (C₁₁H₃).

3-(3,3-dimethylindolin-2-yl)-1H-pyrrolo[2,3-b]pyridine (Procedure 3)

VPC Number LabBook Code          IC₅₀ (eGFP) = 2.1 13 556 CA 2-100 F3-7 (yield = 76%)    IC₅₀ (PSA) = 2.18

t_(R) (HPLC) = 3.52 min       MS (ESI+) m/z = 264.1501                 [(M + H)⁺] HRMS (ESI+): calculated for C₁₇H₁₈N₃, m/z = 264.1495; found, 264.1500 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.51 (s, 1H, H₁₄), 8.18 (dd, J = 4.6, 1.5 Hz, 1H, H₂₀), 7.86 (dd, J = 7.9, 1.1 Hz, 1H, H₁₈), 7.44 (d, J = 2.4 Hz, 1H, H₁₃), 7.02 (d, J = 7.2 Hz, 1H, H₆), 7.00-6.96 (m, 2H, H_(2, 19)), 6.63 (td, J = 7.4, 0.9 Hz, 1H, H₁), 6.60 (d, J = 7.7 Hz, 1H, H₃), 5.92 (d, J = 2.3 Hz, 1H, H₇), 4.74 (d, J = 2.0 Hz, 1H, H₈), 1.38 (s, 3H, H₁₀), 0.74 (s, 3H, H₁₁). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 150.38 (C₄-arom.), 148.74 (C₁₅- arom.), 142.28 (C₂₀H-arom.), 137.95 (C₅-arom.), 127.99 (C₁₈H-arom.), 126.96 (C₂H-arom.), 123.93 (C₁₃H-arom.), 121.97 (C₆H-arom.), 118.98 (C₁₆-arom.), 117.26 (C₁H-arom.), 114.92 (C₁₉H-arom.), 112.80 (C₁₂-arom.), 108.47 (C₃H- arom.), 67.77 (C₈H), 44.77 (C₉), 26.62 (C₁₀H₃), 24.34 (C₁₁H₃).

3-(3,3-dimethylindolin-2-yl)-1H-indole-7-carboxylic acid (Procedure 4)

VPC Number LabBook Code           IC₅₀ (eGFP) = No Data 13 557 CA 2-104 Ap Tmt (yield = 82%)   IC₅₀ (PSA) = No Data

t_(R) (HPLC) = 3.74 min        MS (ESI+) m/z = 307.1442                  [(M + H)⁺] HRMS (ESI+): calculated for C₁₉H₁₉N₂O₂, m/z = 307.1441; found, 304.1442 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 13.01 (br s, 1H, H₂₂), 10.98 (s, 1H, H₁₄), 7.87 (d, J = 7.8 Hz, 1H, H₂₀), 7.74 (d, J = 6.8 Hz, 1H, H₁₈), 7.35 (d, J = 2.3 Hz, 1H, H₁₃), 7.07 (t, J = 7.7 Hz, 1H, H₁₉), 7.02 (d, J = 7.2 Hz, 1H, H₆), 6.98 (td, J = 7.6, 1.1 Hz, 1H, H₂), 6.65-6.58 (m, 2H, H_(1, 3)), 5.93 (br s, 1H, H₇), 4.83 (s, 1H, H₈), 1.39 (s, 3H, H₁₀), 0.73 (s, 3H, H₁₁). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 168.45 (C₂₁O), 150.89 (C₄- arom.), 138.46 (C₅-arom.), 135.63 (C₁₅-arom.), 128.93 (C₁₆-arom.), 127.41 (C₂H-arom.), 125.68 (C₂₀H-arom.), 125.66 (C₁₃H-arom.), 124.20 (C₁₈H- arom.), 122.48 (C₆H-arom.), 118.42 (C₁₉H-arom.), 117.69 (C₁H-arom.), 114.65 (C₁₂-arom.), 113.89 (C₁₇-arom.), 108.90 (C₃H-arom.), 67.76 (C₈H), 45.25 (C₉), 27.08 (C₁₀H₃), 24.91 (C₁₁H₃).

(3-(3,3-dimethylindolin-2-yl)-1H-indole-7-yl)methanol (Procedure 5)

VPC Number LabBook Code           IC₅₀ (eGFP) = 1.6 13 558 CA 2-105 F6-11 (yield = 81%)   IC₅₀ (PSA) = No Data

t_(R) (HPLC) = 3.45 min       MS (ESI+) m/z = 293.1651                  [(M + H)⁺] HRMS (ESI+): calculated for C₁₉H₂₁N₂O, m/z = 293.1648; found, 293.1651 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 10.82 (s, 1H, H₁₄), 7.45 (d, J = 7.8 Hz, 1H, H₂₀), 7.29 (d, J = 2.4 Hz, 1H, H₁₃), 7.05 (d, J = 6.8 Hz, 1H, H₁₈), 7.01 (d, J = 7.2 Hz, 1H, H₆), 6.97 (td, J = 7.6, 1.3 Hz, 1H, H₂), 6.92 (dd, J = 7.8, 6.8 Hz, 1H), 6.61 (m, 2H, H_(1, 3)), 5.84 (d, J = 2.4 Hz, 1H, H₇), 5.14 (t, J = 5.7 Hz, 1H, H₁₈), 4.81 (d, J = 2.1 Hz, 1H, H₈), 4.78 (d, J = 5.7 Hz, 2H, H₂₁), 1.39 (s, 3H, H₁₀), 0.74 (s, 3H, H₁₁). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 150.97 (C₄-arom.), 138.66 (C₅H-arom.), 134.66 (C₁₅-arom.), 127.36 (C₂H-arom.), 127.32 (C₁₆-arom.), 125.92 (C₁₇-arom.), 123.87 (C₁₃H-arom.), 122.43 (C₆H-arom.), 119.41 (C₁₈H-arom.), 118.92 (C₂₀H-arom.), 118.62 (C₁₉H-arom.), 117.57 (C₁H- arom.), 114.36 (C₁₂-arom.), 108.85 (C₃H-arom.), 68.06 (C₈H), 60.82 (C₂₁H₂), 45.19 (C₉), 27.15 (C₁₀H₃), 24.94 (C₁₁H₃).

(3-(3,3-dimethylindolin-2-yl)-1H-pyrrolo[2,3-c]pyridine (Procedure 6)

VPC Number LabBook Code            IC₅₀ (eGFP) = 10.7 13 561 CA 2-121 Ap Tmt (yield = 35%)    IC₅₀ (PSA) = No Data

t_(R) (HPLC) = 3.07 min         MS (ESI+) m/z = 264.1497                    [(M + H)⁺] HRMS (ESI+): calculated for C₁₇H₁₈N₃, m/z = 264.1495; found, 264.1498 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.52 (s, 1H, H₉), 8.73 (s, 1H, H₃), 8.03 (s, 1H, H₅), 7.59 (d, J = 1.7 Hz, 1H, H₈), 7.49 (d, J = 4.3 Hz, 1H, H₆), 7.04-6.95 (m, 2H, H_(11, 15)), 6.66-6.58 (m, 2H, H_(10, 12)), 5.94 (d, J = 1.9 Hz, 1H, H₁₆), 4.78 (d, J = 2.3 Hz, 1H, H₁₇), 1.38 (s, 3H, H₁₉), 0.72 (s, 3H, H₂₀). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 150.34 (C₁₃-arom.), 137.94 (C₁₄-arom.), 137.08 (C₅H-arom.), 134.44 (C₃H-arom.), 133.68 (C₂-arom.), 130.91 (C₁-arom.), 127.79 (C₈H-arom.), 126.96 (C₁₁H-arom.), 121.98 (C₁₅H- arom.), 117.32 (C₁₀H-arom.), 114.54 (C₆H-arom.), 113.67 (C₇-arom.), 108.51 (C₁₂H-arom.), 67.25 (C₁₇H), 44.83 (C₁₈), 26.51 (C₁₉H₃), 24.33 (C₂₀H₃).

(3-(3,3-dimethylindolin-2-yl)-1H-pyrrolo[3,2-b]pyridine (Procedure 6)

VPC Number LabBook Code            IC₅₀ (eGFP) = 2.3 13 560 CA 2-123 Ap Tmt (yield = 72%)    IC₅₀ (PSA) = No Data

t_(R) (HPLC) = 3.05 min         MS (ESI+) m/z = 264.1502                    [(M + H)⁺] HRMS (ESI+): calculated for C₁₇H₁₈N₃, m/z = 264.1495; found, 264.1502 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.16 (s, 1H, H₉), 8.32 (dd, J = 4.6, 1.5 Hz, 1H, H₅), 7.75 (dd, J = 8.2, 1.5 Hz, 1H, H₃), 7.58 (d, J = 2.1 Hz, 1H, H₈), 7.09 (dd, J = 8.2, 4.6 Hz, 1H, H₄), 6.99 (d, J = 7.2 Hz, 1H, H₁₅), 6.96 (td, J = 7.6, 1.3 Hz, 1H, H₁₁), 6.63-6.57 (m, 2H, H_(10, 12)), 5.86 (d, J = 2.7 Hz, 1H, H₁₆), 5.06 (dd, J = 2.8, 0.6 Hz, 1H, H₁₇), 1.51 (s, 3H, H₁₉), 0.72 (s, 3H, H₂₀). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 150.85 (C₁₃H-arom.), 145.29 (C₁-arom.), 142.28 (C₅H-arom.), 139.08 (C₁₄-arom.), 129.27 (C₂-arom.), 127.40 (C₈H-arom.), 127.23 (C₁₁H-arom.), 122.51 (C₁₅H-arom.), 118.77 (C₃H-arom.), 117.72 (C₁₀H-arom.), 116.55 (C₄H-arom.), 115.09 (C₇-arom.), 108.96 (C₁₂H-arom.), 65.98 (C₁₇H), 45.02 (C₁₈), 27.20 (C₁₉H₃), 25.21 (C₂₀H₃).

Cyclohexyl-Hydroindole Moiety

3-(spiro[cyclohexane-1,3′-indolin]-2′-yl)-1H-indole (Procedure 1)

VPC Number LabBook Code            IC₅₀ (eGFP) = 0.8 13 534 CA 2-8 F18-23 (yield = 47%)    IC₅₀ (PSA) = 1.25

t_(R) (HPLC) = 4.39 min       MS (ESI+) m/z = 303.1775                   [(M + H)⁺] HRMS (ESI+): calculated for C₂₁H₂₃N₂, m/z = 303.1856; found, 303.1852 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 10.92 (s, 1H, H₁₂), 7.32 (d, J = 8.0 Hz, 1H, H₁₈), 7.27 (d, J = 2.4 Hz, 1H, H₁₁), 7.17 (d, J = 7.1 Hz, 1H, H₆), 7.02-6.96 (m, 3H, H_(2, 15, 17)), 6.78 (td, J = 7.6, 0.8 Hz, 1H, H₁₆), 6.61 (td, J = 7.4, 1.0 Hz, 1H, H₁), 6.53 (d, J = 7.4 Hz, 1H, H₃), 5.71 (s, 1H, H₇), 4.83 (s, 1H, H₈), 1.82-1.14 (m, 2H, H_(19, 20, 21, 22, 23)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 151.59 (C₄-arom.), 137.65 (C₅- arom.), 137.07 (C₁₃-arom.), 127.58 (C₂H-arom.), 126.78 (C₁₄-arom.), 124.83 (C₁₁H-arom.), 123.58 (C₆H-arom.), 121.08 (C₁₇H-arom.), 120.68 (C₁₅H-arom.), 118.75 (C₁₆H-arom.), 117.00 (C₁H-arom.), 115.58 (C₁₀-arom.), 111.86 (C₁₈H- arom.), 108.32 (C₃H-arom.), 65.96 (C₈H), 48.29 (C₉), 37.43 (C₁₉H₂), 31.94 (C₂₃H₂), 25.99 (C₂₁H₂), 22.96 (C₂₀H₂), 22.81 (C₂₂H₂) .

3-(spiro[cyclohexane-1,3′-indolin]-2′-yl)-5-methyl-1H-indole (Procedure 1)

VPC Number LabBook Code            IC₅₀ (eGFP) = 3.2 13 548 CA 2-72 F12-18 (yield = 69%)    IC₅₀ (PSA) = 4.24

t_(R) (HPLC) = 4.57 min        MS (ESI+) m/z = 317.1950                   [(M + H)⁺] HRMS (ESI+): calculated for C₂₂H₂₅N₂, m/z = 317.2012; found, 317.2008 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 10.78 (d, J = 1.4 Hz, 1H, H₉), 7.22- 7.19 (m, 2H, , H_(3, 8)), 7.17 (d, J = 7.6 Hz, 1H, H₁₅), 7.00 (td, J = 7.6, 1.2 Hz, 1H, H₁₁), 6.82 (dd, J = 8.3, 1.5 Hz, 1H, H₄), 6.75 (br s, 1H, H₆), 6.62 (td, J = 7.4, 1.0 Hz, 1H, H₁₀), 6.53 (d, J = 7.6 Hz, 1H, H₁₂), 5.65 (s, 1H, H₁₆), 4.78 (s, 1H, H₁₇), 2.18 (s, 3H, H₂₄), 1.80-1.16 (m, 10H, H_(19, 20, 21, 22, 23)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 151.69 (C₁₃-arom.), 137.72 (C₁₄- arom.), 135.43 (C₂-arom.), 127.45 (C₁₁H-arom.), 127.03 (C₅-arom.), 126.85 (C₁- arom.), 124.83 (C₈H-arom.), 123.64 (C₁₅H-arom.), 122.62 (C₄H-arom.), 120.51 (C₆H-arom.), 116.95 (C₁₀H-arom.), 114.98 (C₇-arom.), 111.51 (C₃H-arom.), 108.44 (C₁₂H-arom.), 66.18 (C₁₇H), 48.25 (C₁₈), 37.22 (C₁₉H₂), 31.96 (C₂₃H₂), 26.00 (C₂₁H₂), 23.01 (C₂₀H₂), 22.75 (C₂₂H₂), 21.88 (C₂₄H₃).

3-(spiro[cyclohexane-1,3′-indolin]-2′-yl)-7-methyl-1H-indole (Procedure 1)

VPC Number LabBook Code            IC₅₀ (eGFP) = 1.7 13 549 CA 2-73 F9-15 (yield = 72%)    IC₅₀ (PSA) = 2.57

t_(R) (HPLC) = 4.58 min       MS (ESI+) m/z = 317.1932                   [(M + H)⁺] HRMS (ESI+): calculated for C₂₂H₂₅N₂, m/z = 317.2012; found, 317.2022 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 10.88 (s, 1H, H₉), 7.25 (d, J = 2.5 Hz, 1H, H₈), 7.16 (d, J = 7.0 Hz, 1H, H₁₅), 6.98 (td, J = 7.6, 1.2 Hz, 1H, H₁₁), 6.85 (d, J = 7.9 Hz, 1H, H₆), 6.80 (d, J = 7.0 Hz, 1H, H₄), 6.70 (t, J = 7.6 Hz, 1H, H₅), 6.60 (td, J = 7.4, 1.0 Hz, 1H, H₁₀), 6.53 (dd, J = 7.6, 0.4 Hz, 1H, H₁₂), 5.67 (s, 1H, H₁₆), 4.82 (s, 1H, H₁₇), 2.43 (s, 3H, H₂₄), 1.83-1.17 (m, 10H, H_(19, 20, 21, 22, 23)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 151.60 (C₁₃-arom.), 137.67 (C₁₄- arom.), 136.53 (C₂-arom.), 127.56 (C₁₁H-arom.), 126.48 (C₁-arom.), 124.52 (C₈H-arom.), 123.60 (C₁₅H-arom.), 121.61 (C₄H-arom.), 120.80 (C₃-arom.), 118.95 (C₅H-arom.), 118.30 (C₆H-arom.), 116.98 (C₁₀H-arom.), 116.02 (C₇- arom.), 108.33 (C₁₂H-arom.), 66.00 (C₁₇H), 48.28 (C₁₈), 37.44 (C₁₉H₂), 31.95 (C₂₃H₂), 26.00 (C₂₁H₂), 22.97 (C₂₀H₂), 22.80 (C₂₂H₂), 17.25 (C₂₄H₃).

3-(spiro[cyclohexane-1,3′-indolin]-2′-yl)-6-(benzyloxy)-1H-indole (Procedure 1)

VPC Number LabBook Code            IC₅₀ (eGFP) = 11.8 13 550 CA 2-76 F13-24 (yield = 55%)    IC₅₀ (PSA) = No Data

t_(R) (HPLC) = 5.07 min        MS (ESI+) m/z = 409.2254                   [(M + H)⁺] HRMS (ESI+): calculated for C₂₈H₂₉N₂O, m/z = 409.2274; found, 409.2278 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 10.72 (d, J = 1.7 Hz, 1H, H₁₂), 7.46-7.42 (m, 2H, H_(22, 26)), 7.41-7.36 (m, 2H, H_(23, 25)), 7.34-7.30 (m, 1H, , H₂₄), 7.17-7.12 (m, 2H, , H_(6, 11)), 6.98 (td, J = 7.6, 1.2 Hz, 1H, H₂), 6.89 (d, J = 2.2 Hz, 1H, H₁₅), 6.82 (br d, J = 8.7 Hz, 1H, H₁₈), 6.60 (td, J = 7.4, 1.0 Hz, 1H, H₁), 6.54-6.50 (m, 2H, , H₃₋₁₇), 5.67 (s, 1H, H₇), 5.07 (s, 2H, H₂₀), 4.76 (s, 1H, H₈), 1.80-1.15 (m, 10H, H_(19, 20, 21, 22, 23)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 154.56 (C₁₆-arom.), 151.55 (C₄- arom.), 138.16 (C₂₁-arom.), 137.71 (C₅-arom.), 137.65 (C₁₃-arom.), 128.82 (C_(23, 25)H-arom.), 128.04 (C₂₄H-arom.), 127.88 (C_(22, 26)H-arom.), 127.58 (C₂H- arom.), 123.67 (C₆H-arom.), 123.54 (C₁₁H-arom.), 121.34 (C₁₄-arom.), 121.31 (C₁₈H-arom.), 116.98 (C₁H-arom.), 115.58 (C₁₀-arom.), 109.47 (C₁₇H-arom.), 108.32 (C₃H-arom.), 96.43 (C₁₅H-arom.), 69.87 (C₂₀H₂), 66.04 (C₈H), 48.22 (C₉), 37.40 (C₁₉H₂), 31.91 (C₂₃H₂), 25.99 (C₂₁H₂), 22.95 (C₂₀H₂), 22.83 (C₂₂H₂).

3-(spiro[cyclohexane-1,3′-indolin]-2′-yl)-6-hydroxy-1H-indole (Procedure 2)

VPC Number LabBook Code           IC₅₀ (eGFP) = 15.5 13 551 CA 2-83 F2-7 (yield = 38%)    IC₅₀ (PSA) = No Data

t_(R) (HPLC) = 3.57 min        MS (ESI+) m/z = 319.1824                  [(M + H)⁺] HRMS (ESI+): calculated for C₂₁H₂₃N₂O, m/z = 319.1805; found, 319.1802 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 10.51 (d, J = 1.5 Hz, 1H, H₁₂), 8.79 (s, 1H, H₂₄), 7.15 (d, J = 7.0 Hz, 1H, H₆), 7.04 (d, J = 2.3 Hz, 1H, H₁₁), 6.97 (td, J = 7.6, 1.2 Hz, 1H, H₂), 6.72 (d, J = 8.5 Hz, 1H, H₁₈), 6.67 (d, J = 2.0 Hz, 1H, H₁₅), 6.59 (td, J =7.4, 1.0 Hz, 1H, H₁), 6.51 (d, J = 7.7 Hz, 1H, H₃), 6.30 (dd, J = 8.6, 2.2 Hz, 1H, H₁₇), 5.64 (s, 1H, H₇), 4.73 (s, 1H, H₈), 1.81- 1.16 (m, 10H, H_(19, 20, 21, 22, 23)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 153.10 (C₁₆-arom.), 151.57 (C₄- arom.), 138.21 (C₁₃-arom.), 137.70 (C₅-arom.), 127.52 (C₂H-arom.), 123.55 (C₆H-arom.), 122.74 (C₁₁H-arom.), 121.06 (C₁₈H-arom.), 120.26 (C₁₄-arom.), 116.91 (C₁H-arom.), 115.43 (C₁₀-arom.), 109.35 (C₁₇H-arom.), 108.29 (C₃H- arom.), 96.85 (C₁₅H-arom.), 66.16 (C₈H), 48.18 (C₉), 37.38 (C₁₉H₂), 31.91 (C₂₃H₂), 26.01 (C₂₁H₂), 22.97 (C₂₀H₂), 22.83 (C₂₂H₂) .

3-(spiro[cyclohexane-1,3′-indolin]-2′-yl)-7-hydroxy-1H-indole (Procedure 2)

VPC Number LabBook Code              IC₅₀ (eGFP) = 1.1 13 552 CA 2-84 Precipitate (yield = 28%)    IC₅₀ (PSA) = 1.14

t_(R) (HPLC) = 3.81 min         MS (ESI+) m/z = 319.1728                     [(M + H)⁺] HRMS (ESI+): calculated for C₂₁H₂₃N₂O, m/z = 319.1805; found, 319.1814 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 10.72 (d, J = 1.8 Hz, 1H, H₁₂), 9.42 (s, 1H, H₂₄), 7.14 (d, J = 7.1 Hz, 1H, H₆), 7.12 (d, J = 2.5 Hz, 1H, H₁₁), 6.97 (td, J = 7.6, 1.2 Hz, 1H, H₂), 6.59 (m, 2H, H_(1, 17)), 6.52 (m, 2H, H_(3, 18)), 6.42 (dd, J = 7.4, 0.8 Hz, 1H, H₁₆), 5.65 (s, 1H, H₇), 4.79 (s, 1H, H₈), 1.82- 1.16 (m, 10H, H_(19, 20, 21, 22, 23)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 151.60 (C₄-arom.), 143.87 (C₁₅- arom.), 137.66 (C₅-arom.), 128.78 (C₁₄-arom.), 127.50 (C₂H-arom.), 127.06 (C₁₃-arom.), 124.10 (C₁₁H-arom.), 123.60 (C₆H-arom.), 119.38 (C₁₇H-arom.), 116.93 (C₁H-arom.), 115.94 (C₁₀-arom.), 111.78 (C₁₈H-arom.), 108.29 (C₃H- arom.), 105.41 (C₁₆H-arom.), 65.88 (C₈H), 48.33 (C₉), 37.45 (C₁₉H₂), 31.93 (C₂₃H₂), 26.00 (C₂₁H₂), 22.98 (C₂₀H₂), 22.79 (C₂₂H₂).

Unexpected Compounds—General Procedure 7

Phenylhydrazine (1.0 eq) aldehyde (isobutyraldehyde or cyclohexanecarboxaldehyde) (1.0 eq) were diluted in AcOH (0.1 M). The mixture was heated at 65° C. for 2 h (until complete conversion). Then, 7-azaindole or 1,5,6,7-Tetrahydro-4H-indol-4-one (1.0 eq) was added and the reaction mixture was stirred additional 24 h at 100° C. (until complete conversion). Acetic acid was removed under vacuo. Then, the residue was poured with H₂O and neutralized at pH 7 with sat. NaHCO₃ solution. The aqueous layer was extracted with AcOEt (×3) and organic layers were combined, washed with brine, dried over Na₂SO₄ and evaporated under reduced pressure. Then, crude was purified by automated combi-flash to afford the good compound.

3-(3,3-dimethyl-3H-indol-2-yl)-1H-pyrrolo[2,3-b]pyridine (Procedure 7)

VPC Number LabBook Code            IC₅₀ (eGFP) = 0.7 13 537 CA 2-39 F9-15 (yield = 25%)    IC₅₀ (PSA) = 0.81

t_(R) (HPLC) = 3.17 min         MS (ESI+) m/z = 262.1345                   [(M + H)⁺] HRMS (ESI+): calculated for C₁₇H₁₆N₃, m/z = 262.1339; found, 262.1345 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 12.40 (s, 1H, H₁₄), 8.94 (dd, J = 7.9, 1.7 Hz, 1H, H₁₈), 8.40 (s, 1H, H₁₃), 8.35 (dd, J = 4.6, 1.6 Hz, 1H, H₂₀), 7.56 (d, J = 7.5 Hz, 1H, H₃), 7.49 (d, J = 6.8 Hz, 1H, H₆), 7.32 (td, J = 7.6, 1.2 Hz, 1H, H₂), 7.28 (dd, J = 7.9, 4.7 Hz, 1H, H₁₉), 7.20 (td, J = 7.4, 1.0 Hz, 1H, H₁), 1.54 (s, 6H, H_(10,11)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 180.97 (C₈), 154.77 (C₄-arom.), 149.39 (C₁₅-arom.), 146.90 (C₅-arom.), 144.50 (C₂₀H-arom.), 131.69 (C₁₈H- arom.), 130.45 (C₁₃H-arom.), 127.92 (C₂H-arom.), 124.80 (C₁H-arom.), 121.61 (C₆H-arom.), 119.71 (C₃H-arom.), 119.05 (C₁₆-arom.), 117.73 (C₁₉H-arom.), 108.26 (C₁₂-arom.), 53.39 (C₉), 25.82 (C_(10, 11)).

Tetrahydro-3-(3,3-dimethyl-3H-indol-2-yl)-1H-indol-4-one (Procedure 7)

VPC Number LabBook Code            IC₅₀ (eGFP) = No Data 13 539 CA 2-48 F19-22 (yield = 9%)    IC₅₀ (PSA) = No Data

t_(R) (HPLC) = 3.54 min       MS (ESI+) m/z = 279.1498                   [(M + H)⁺] HRMS (ESI+): calculated for C₁₈H₁₉N₂O, m/z = 279.1492; found, 279.1498 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 12.27 (s, 1H, H₁₄), 7.54-7.48 (m, 2H, H_(3, 6)), 7.33 (td, J = 7.6, 1.3 Hz, 1H, H₂), 7.22 (td, J = 7.4, 1.0 Hz, 1H, H₁), 7.05 (d, J = 1.8 Hz, 1H, H₁₃), 2.85 (t, J = 6.1 Hz, 2H, H₁₇), 2.39 (t, J = 6.4 Hz, 2H, H₁₇), 2.09-2.02 (m, 2H, H₁₈), 1.46 (s, 6H, H_(10, 11)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 193.35 (C₂₀O), 176.21 (C₈), 153.76 (C₄-arom.), 148.19 (C₁₅-arom.), 147.25 (C₅-arom.), 128.13 (C₂H-arom.), 126.38 (C₁₂-arom.), 125.40 (C₁H-arom.), 121.96 (C₆H-arom.), 121.76 (C₁₆-arom.), 119.76 (C₃H-arom.), 109.82 (C₁₃H-arom.), 52.57 (C₉), 38.25 (C₁₉H₂), 25.49 (C_(10, 11)H₃), 23.71 (C₁₈H₂), 22.70 (C₁₇H₂).

3-(spiro[cyclohexane-1,3′-indolin]-2′-yl)-1H-pyrrolo[2,3-b]pyridine (Procedure 7)

VPC Number LabBook Code             IC₅₀ (eGFP) = 6.6 13 559 CA 2-110 F18-27 (yield = 23%)    IC₅₀ (PSA) = No Data

t_(R) (HPLC) = 3.70 min        MS (ESI+) m/z = 302.1654                    [(M + H)⁺] HRMS (ESI+): calculated for C₂₀H₂₀N₃, m/z = 302.1652; found, 302.1654 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 12.39 (s, 1H, H₁₇), 9.00 (dd, J = 7.9, 1.7 Hz, 1H, H₂₁), 8.45 (d, J = 2.0 Hz, 1H, H₁₆), 8.35 (dd, J = 4.6, 1.6 Hz, 1H, H₂₃), 7.87 (d, J = 7.3 Hz, 1H, H₆), 7.62 (dd, J = 7.6, 0.6 Hz, 1H, H₃), 7.38 (td, J = 7.6, 1.0 Hz, 1H, H₂), 7.27 (dd, J = 7.9, 4.7 Hz, 1H, H₂₂), 7.17 (td, J = 7.5, 1.1 Hz, 1H, H₁), 2.34-2.25 (m, 2H, H₁₀), 2.07-1.77 (m, 6H, H_(11, 12, 13)), 1.32-1.26 (m, 2H, H₁₄). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 180.61 (C₈), 155.41 (C₄-arom.), 149.19 (C₁₈-arom.), 145.63 (C₅-arom.), 144.45 (C₂₃H-arom.), 132.08 (C₂₁H- arom.), 130.23 (C₁₆H-arom.), 127.95 (C₂H-arom.), 124.74 (C₆H-arom.), 123.93 (C₁H-arom.), 120.36 (C₃H-arom.), 119.45 (C₁₉-arom.), 117.71 (C₂₂H-arom.), 107.92 (C₁₅-arom.), 57.86 (C₉), 33.53 (C_(10, 14)H₂), 24.81 (C₁₂H₂), 21.89 (C_(11, 13)H₂).

Quinoline Moiety—General Procedure 9

In microwave vessel, quinoline (2.0 eq) and indole (1.0 eq) were mixed together and the system was sealed and placed under nitrogen, after a purge with vacuum/N₂ (3 times). Then, HCl solution 4 M in 1,4-dioxane (1.2 eq) was added with the needle immersed in the mixture (exothermic reaction). The reaction mixture was heated with microwave during 2 h at 160° C. The reaction mixture was taken up with a minimum of MeOH and when the residue was dissolved, it was transferred in mixture of AcOEt and saturated NaHCO₃ solution. The resulting solution was extracted and the aqueous phase was washed with AcOEt (×2). The organic layers were combined, washed with 0.01 M critic acid solution, saturated NaHCO₃ solution, dried over Na₂SO₄ and concentrated to dryness under reduced pressure. Finally, the crude was purified by automated combi-flash to afford the good compound.

General Procedure 10

Halogenated-compound (1.0 eq), boronic acid (or boronate) (1.1 eq) and Pd(PPh₃)₄ (10% mol) was added in microwave vessel (10-20 mL). The vial was sealed with a cap and the system was purged with vacuum and placed under N₂. Then, the solids were dissolved in mixture of Toluene/EtOH (4.5: 2.0, 0.11 M) and purged with vacuum/N₂ one more time. Then, a solution of K₂CO₃ (3.0 eq) in H₂O (1.8 M) was added. The reaction mixture was stirred and heated overnight at 95° C. with oil bath. The reaction mixture was filtered on plug of celite. The filtrate was was poured with water and was extracted with AcOEt (×3). The organic layers were combined, washed with brine, dried over Na₂SO₄ and evaporated under reduced pressure. The residue was taken up in DCM/TFA (5: 5) for 2 h at r.t. The solvents were evaporated under reduced pressure. The residue was then neutralized with saturated NaHCO₃ solution and extracted with AcOEt (×2). The organic layers were washed, dried and concentrated in vacuo. The residue was precipitate in DCM or purified by automated combi-flash to afford the good compound.

2-(1H-indol-3-yl)-4-methylquinoline

VPC Number LabBook Code          IC₅₀ (eGFP) = 5.6 13 547 CA 2-69 F6-11 (yield = 62%)    IC₅₀ (PSA) = No Data

t_(R) (HPLC) = 3.20 min         MS (ESI+) m/z = 259.1243                 [(M + H)⁺] Mp = 168-180° C. HRMS (ESI+): calculated for C₁₈H₁₅N₂, m/z = 259.1230; found, 259.1237 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.63 (s, 1H, H₁₄), 8.90- 8.85 (m, 1H, H₂₀), 8.32 (d, J = 2.8 Hz, 1H, H₁₃), 8.04-7.98 (m, 2H, H_(3, 6)), 7.94 (d, J = 0.9 Hz, 1H, H₉), 7.71 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H, H₂), 7.53-7.44 (m, 2H, H_(1, 17)), 7.24-7.16 (m, 2H, H_(18, 19)), 2.71 (d, J = 0.8 Hz, 3H, H₁₂). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 155.74 (C₈-arom.), 148.21 (C₄- arom.), 143.61 (C₁₀-arom.), 137.64 (C₁₅-arom.), 129.51 (C₂H-arom.), 129.39 (C₃H-arom.), 127.98 (C₁₃H-arom.), 126.42 (C₅-arom.), 126.13 (C₁₆- arom.), 125.18 (C₁H-arom.), 124.35 (C₆H-arom.), 123.12 (C₂₀H-arom.), 122.48 (C₁₈H-arom.), 120.68 (C₁₉H-arom.), 119.90 (C₉H-arom.), 115.97 (C₁₁-arom.), 112.16 (C₁₇H-arom.), 18.76 (C₁₂H₃).

2-(7-methoxy-1H-indol-3-yl)-4-methylquinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 0.6 13 554 CA 2-87 F7-10 (yield = 22%) IC₅₀ (PSA) = 0.67

t_(R) (HPLC) = 3.37 min         MS (ESI+) m/z = 289.1336 [(M + H)⁺] Mp = 146-152° C. HRMS (ESI+): calculated for C₁₉H₁₇N₂O, m/z = 289.1335; found, 289.1335 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.73 (s, 1H, H₁₄), 8.45 (d, J = 8.0 Hz, 1H, H₂₀), 8.21 (d, J = 2.9 Hz, 1H, H₁₃), 8.03-7.99 (m, 2H, H_(3,6)), 7.95 (d, J = 0.8 Hz, 1H, H₉), 7.70 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H, H₂), 7.50 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H, H₁), 7.11 (t, J = 7.9 Hz, 1H, H₁₉), 6.79 (d, J = 7.5 Hz, 1H, H₁₈), 3.97 (s, 3H, H₂₂), 2.70 (d, J = 0.8 Hz, 3H, H₁₂). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 155.23 (C₈-arom.), 147.71 (C₄- arom.), 146.06 (C₁₇-arom.), 143.11 (C₁₀-arom.), 129.00 (C₂H-arom.), 128.91 (C₃H-arom.), 127.23 (C₁₅-arom.), 127.14 (C₁₆-arom.), 126.97 (C₁₃H-arom.), 125.95 (C₅-arom.), 124.69 (C₁H-arom.), 123.85 (C₆H-arom.), 120.76 (C₁₉H- arom.), 119.52 (C₉H-arom.), 116.09 (C₁₁-arom.), 115.37 (C₂₀H-arom.), 102.58 (C₁₈H-arom.), 55.18 (C₂₂H₃), 18.24 (C₁₂H₃).

2-(1H-indol-3-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 0.06 13 562 CA 2-128 F8-12 (yield = 46%) IC₅₀ (PSA) = 0.14

t_(R) (HPLC) = 2-91 min         MS (ESI+) m/z = 245.1073 [(M + H)⁺] Mp = 184-187° C. HRMS (ESI+): calculated for C₁₇H₁₃N₂, m/z = 245.1073; found, 245.1075 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.65 (s, 1H, H₁₃), 8.88 (d, J = 8.5 Hz, 1H, H₁₉), 8.35 (d, J = 2.7 Hz, 1H, H₁₂), 8.26 (d, J = 8.6 Hz, 1H, H₁₀), 8.06 (d, J = 8.7 Hz, 1H, H₉), 8.04 (d, J = 8.3 Hz, 1H, H₃), 7.89 (d, J = 7.9 Hz, 1H, H₆), 7.72 (t, J = 7.6 Hz, 1H, H₂), 7.51-7.46 (m, 2H, H_(1,16)), 7.24-7.18 (m, 2H, H_(17,18)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 155.56 (C₈-arom.), 147.75 C₄- arom.s), 137.21 (C₁₄-arom.), 135.59 (C₁₀H-arom.), 129.34 (C₂H-arom.), 128.34 (C₃H-arom.), 127.79 (C₆H-arom.), 127.61 (C₁₂H-arom.), 125.80 (C₅-arom.), 125.58 (C₁₅-arom.), 124.88 (C₁H-arom.), 122.57 (C₁₉H-arom.), 122.08 (C₁₇H- arom.), 120.31 (C₁₈H-arom.), 119.21 (C₉H-arom.), 115.49 (C₁₁H-arom.), 111.73 (C₁₆H-arom.).

2-(7-fluoro-1H-indol-3-yl)quinoline (Procedure 9)

VPC Number LabBook Code IC₅₀ (eGFP) = 1.6 13 569 CA 3-45 F13-23 Precipitate IC₅₀ (PSA) = Not Tested (yield = 34%)

t_(R) (HPLC) = 3.02 min        MS ((ESI+) m/z = 263.1009 [(M + H)⁺] Mp = 152-154° C. HRMS (ESI+): calculated for C₁₇H₁₂FN₂, m/z = 263.0979; found, 263.0976 ¹H NMR (500 MHz, DMSO-d₆): δ (ppm) = 12.17 (s, 1H, H₁₃), 8.71 (d, J = 8.0 Hz, 1H, H₁₉), 8.44 (d, J = 2.8 Hz, 1H, H₁₂), 8.29 (d, J = 8.7 Hz, 1H, H₁₀), 8.10 (d, J = 8.7 Hz, 1H, H₉), 8.05 (d, J = 8.3 Hz, 1H, H₃), 7.91 (d, J = 7.5 Hz, 1H, H₆), 7.73 (t, J = 7.5 Hz, 1H, H₂), 7.51 (t, J = 7.5 Hz, 1H, H₁), 7.21-7.15 (m, 1H, H₁₈), 7.06 (dd, J = 11.4, 7.8 Hz, 1H, H₁₇). ¹³C NMR (126 MHz, DMSO-d₆): δ (ppm) = 155.50 (C₈-arom.), 149.63 (d, J = 243.4 Hz, C₁₆-arom.), 148.13 (C₄-arom.), 136.29 (C₁₀H-arom.), 129.92 (C₂H- arom.), 129.85 (d, J = 5.2 Hz, C₁₅-arom.), 129.18 (C₁₂H-arom.), 128.90 (C₃H- arom.), 128.14 (C₆H-arom.), 126.41 (C₅-arom.), 125.63 (C₁H-arom.), 125.52 (d, J = 13.2 Hz, C₁₄-arom.), 121.14 (d, J = 6.2 Hz, C₁₈H-arom.), 119.76 (C₉H- arom.), 119.30 (d, J = 3.0 Hz, C₁₉H-arom.), 116.97 (d, J = 1.3 Hz, C₁₁-arom.), 107.43 (d, J = 15.6 Hz, C₁₇H-arom.).

2-(7-ethyl-1H-indol-3-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 0.2 13 567 CA 3-46 P2 F6-13 (yield = 45%) IC₅₀ (PSA) = 0.23

t_(R) (HPLC) = 3.16 min        MS (ESI+) m/z = 273.1719 [(M + H)⁺] Mp = 159-162° C. HRMS (ESI+): calculated for C₁₉H₁₇N₂, m/z = 273.1386; found, 273.1389 ¹H NMR (500 MHz, DMSO-d₆): δ (ppm) = 11.63 (s, 1H, H₁₃), 8.73 (d, J = 7.9 Hz, 1H, H₁₉), 8.34 (d, J = 2.9 Hz, 1H, H₁₂), 8.25 (d, J = 8.7 Hz, 1H, H₁₀), 8.09 (d, J = 8.7 Hz, 1H, H₉), 8.03 (d, J = 8.4 Hz, 1H, H₃), 7.88 (d, J = 7.2 Hz, 1H, H₆), 7.71 (ddd, J = 8.3, 7.0, 1.4 Hz, 1H, H₂), 7.48 (ddd, J = 7.5, 6.5, 1.0 Hz, 1H, H₁), 7.15 (t, J = 7.8 Hz, 1H, H₁₈), 7.05 (d, J = 6.9 Hz, 1H, H₁₇), 2.93 (q, J = 7.5 Hz, 2H, H₂₀), 1.32 (t, J = 7.5 Hz, 3H, H₂₁). ¹³C NMR (126 MHz, DMSO-d₆): δ (ppm) = 156.14 (C₈-arom.), 148.27 (C₄- arom.), 136.38 (C₁₄-arom.), 135.97 (C₁₀H-arom.), 129.76 (C₂H-arom.), 128.86 (C₃H-arom.), 128.07 (C₆H-arom.), 127.98 (C₁₂H-arom.), 127.62 (C₁₆-arom.), 126.28 (C₅-arom.), 126.00 (C₁₅-arom.), 125.30 (C₁H-arom.), 121.28 (C₁₇H- arom.), 121.08 (C₁₈H-arom.), 120.74 (C₁₉H-arom.), 119.80 (C₉H-arom.), 116.39 (C₁₁-arom.), 24.09 (C₂₀H₂), 15.01 (C₂₁H₃).

2-(2-methyl-1H-indol-3-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 20.0 13 570 CA 3-47 F35-40 (yield = 29%) IC₅₀ (PSA) = Not Tested

t_(R) (HPLC) = 2.91 min         MS (ESI+) m/z = 259.1435 [(M + H)⁺] Mp = 67-75° C. HRMS (ESI+): calculated for C₁₈H₁₅N₂, m/z = 259.1230; found, 259.1230 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.48 (s, 1H, H₁₃), 8.34 (d, J = 8.6 Hz, 1H, H₁₀), 8.21 (dd, J = 6.5, 2.4 Hz, 1H, H₁₉), 8.01 (d, J = 8.4 Hz, 1H, H₃), 7.94 (d, J = 7.6 Hz, 1H, H₆), 7.85 (d, J = 8.6 Hz, 1H, H₉), 7.73 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H, H₂), 7.52 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H, H₁), 7.40 (dd, J = 6.4, 2.2 Hz, 1H, H₁₆), 7.15-7.11 (m, 2H, H_(17,18)), 2.77 (s, 3H, H₂₀). ¹³C NMR (126 MHz, DMSO-d₆): δ (ppm) = 156.19 (C₈-arom.), 148.41 (C₄- arom.), 137.38 (C₁₂-arom.), 136.27 (C₁₀H-arom.), 135.74 (C₁₄-arom.), 129.85 (C₂H-arom.), 128.87 (C₃H-arom.), 128.13 (C₆H-arom.), 127.46 (C₁₅-arom.), 125.97 (C₅-arom.), 125.58 (C₁H-arom.), 121.69 (C₉H-arom.), 121.53 (C₁₇H- arom.) 120.38 (C₁₈H-arom.), 120.18 (C₁₉H-arom.), 112.46 (C₁₁-arom.), 111.34 (C₁₆H-arom.), 14.36 (C₂₀H₃).

2-(6-bromo-1H-indol-3-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 1.3 13 568 CA 3-49 F44-63 Precipitate (yield = 46%) IC₅₀ (PSA) = 1.56

t_(R) (HPLC) = 3.29 min           MS (ESI+) m/z = 323.0190,                     325.0174 [(M + H)⁺] Mp = 189-194° C. (HRMS (ESI+): calculated for C₁₇H₁₂BrN₂, m/z = 323.0178, 325.0159; found, 323.0183, 325.0167 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.79 (s, 1H, H₁₃), 8.84 (d, J = 8.5 Hz, 1H, H₁₉), 8.39 (d, J = 2.8 Hz, 1H, H₁₂), 8.28 (d, J = 8.7 Hz, 1H, H₁₀), 8.05 (m, 2H, H_(3,9)), 7.90 (d, J = 7.5 Hz, 1H, H₆), 7.72 (t, J = 7.5 Hz, 1H, H₂), 7.67 (d, J = 1.6 Hz, 1H, H₁₆), 7.50 (t, J = 7.5 Hz, 1H, H₁), 7.34 (dd, J = 8.5, 1.8 Hz, 1H, H₁₈). ¹³C NMR (126 MHz, DMSO-d₆): δ (ppm) = 155.52 (C₈-arom.), 148.15 (C₄-arom.), 138.58 (C₁₄-arom.), 136.27 (C₁₀H-arom.), 129.91 (C₂H-arom.), 129.11 (C₁₂H-arom.), 128.88 (C₃H-arom.), 128.13 (C₆H-arom.), 126.37 (C₅-arom.), 125.59 (C₁H-arom.), 125.11 (C₁₅-arom.), 124.82 (C₁₉H-arom.), 123.65 (C₁₈H-arom.), 119.57 (C₉H-arom.), 116.11 (C₁₁-arom.), 115.31 (C₁₇-arom.), 114.82 (C₁₆H-arom).

2-(1-methyl-1H-indol-3-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 1.1 13 571 CA 3-56 Precipitate (yield = 53%) IC₅₀ (PSA) = Not Tested

t_(R) (HPLC) = 3.05 min      MS (ESI+) m/z = 259.1355                [(M + H)⁺] Mp = 175-179° C. HRMS (ESI+): calculated for C₁₈H₁₅N₂, m/z = 259.1230; found, 259.1232 ¹H NMR (500 MHz, DMSO-d₆): δ (ppm) = 8.88 (d, J = 8.5 Hz, 1H, H₁₉), 8.34 (s, 1H, H₁₂), 8.27 (d, J = 8.7 Hz, 1H, H₁₀), 8.03 (d, J = 8.3 Hz, 1H, H₃), 7.98 (d, J = 8.7 Hz, 1H, H₉), 7.89 (d, J = 7.2 Hz, 1H, H₆), 7.72 (t, J = 7.6 Hz, 1H, H₂), 7.54 (d, J = 7.5 Hz, 1H, H₁₆), 7.49 (t, J = 7.6 Hz, 1H, H₂), 7.29-7.26 (m, 2H, H_(17, 18)), 3.91 (s, 3H, H₂₀). ¹³C NMR (126 MHz, DMSO-d₆): δ (ppm) = 155.64 (C₈-arom.), 148.28 (C₄- arom.), 138.16 (C₁₄-arom.), 136.21 (C₁₀H-arom.), 132.24 (C₁₂H-arom.), 129.88 (C₂H-arom.), 128.84 (C₃H-arom.), 128.11 (C₆H-arom.), 126.43 (C₁₅- arom.), 126.27 (C₅-arom.), 125.40 (C₁H-arom.), 123.16 (C₁₉H-arom.), 122.66 (C₁₇H-arom.), 121.07 (C₁₈H-arom.), 119.50 (C₉H-arom.), 115.00 (C₁₁-arom.), 110.58 (C₁₆H-arom.), 33.40 (C₂₀H₃-arom.).

2-(1H-indazol-1-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 0.7 13 572 CA 3-59 F11 (yield = 25%) IC₅₀ (PSA) = Not Tested

t_(R) (HPLC) = 4.44 min      MS (ESI+) m/z = 246.1019                [(M + H)⁺] Mp = 91-96° C. HRMS (ESI+): calculated for C₁₆H₁₂N₃, m/z = 246.1026; found, 246.1028 ¹H NMR (500 MHz, CDCl₃): δ (ppm) = 9.18 (d, J = 8.5 Hz, 1H, H₁₆), 8.28 (d, J = 9.0 Hz, 1H, H₉), 8.25-8.21 (m, 2H, H_(10, 11)), 8.11 (d, J = 8.4 Hz, 1H, H₃), 7.82-7.77 (m, 2H, H_(6, 19)), 7.72 (ddd, J = 8.3, 7.0, 1.4 Hz, 1H, H₂), 7.59 (ddd, J = 8.3, 7.0, 1.0 Hz, 1H, H₁₇), 7.48 (ddd, J = 8.1, 7.0, 1.3 Hz, 1H, H₁), 7.32 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H, H₁₈). ¹³C NMR (126 MHz, CDCl₃): δ (ppm) = 152.95 (C₈-arom.), 146.66 (C₄- arom.), 139.00 (C₁₄-arom.), 138.46 (C₁₀H-arom.), 137.18 (C₁₁H-arom.), 130.05 (C₂H-arom.), 128.36 (C₃H-arom ), 128.22 (C₁₇H-arom.), 127.67 (C₆H- arom.), 126.28 (C₅-arom.), 126.14 (C₁₅-arom.), 125.51 (C₁H-arom.), 122.95 (C₁₈H-arom.), 120.82 (C₁₉H-arom.), 116.03 (C₁₆H-arom.), 113.48 (C₉H- arom.).

2-(7-methyl-1H-indol-3-yl)quinoline (Procedure 9)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.095 13 566 CA 3-67 Precipitate (yield = 48%) IC₅₀ (PSA) = 0.056

t_(R) (HPLC) = 3.10 min      MS (ESI+) m/z = 259.1255                [(M + H)⁺] Mp = 146-150° C. HRMS (ESI+): calculated for C₁₈H₁₅N₂, m/z = 259.1230; found, 259.1229 ¹H NMR (500 MHz, DMSO-d₆): δ (ppm) = 11.63 (s, 1H), 8.72 (d, J = 7.9 Hz, 1H), 8.35 (d, J = 2.8 Hz, 1H), 8.25 (d, J = 8.7 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.74-7.68 (m, 1H), 7.48 (t, J = 7.4 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 2.54 (s, 3H). ¹³C NMR (126 MHz, DMSO-d₆): δ (ppm) = 156.14, 148.27, 137.19, 135.98, 129.77, 128.86, 128.08, 128.02, 126.28, 125.82, 125.31, 123.10, 121.27, 120.98, 120.70, 119.79, 116.41, 17.27.

2-(5-methyl-1H-indol-3-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 3.2 13 577 CA 3-73 Precipitate (yield = 55%) IC₅₀ (PSA) = 1.73

t_(R) (HPLC) = 3.12 min      MS (ESI+) m/z = 259.1248                [(M + H)⁺] HRMS (ESI+): calculated for C₁₈H₁₅N₂, m/z = 259.1230; found, 259.1218 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 12.64 (s, 1H, H₁₃), 8.97 (s, 1H, H₁₂), 8.89 (d, J = 8.1 Hz, 1H, H₁₀), 8.58 (d, J = 8.2 Hz, 1H, H₃), 8.42 (d, J = 8.9 Hz, 1H, H₉), 8.22 (d, J = 8.0 Hz, 1H, H₆), 8.10 (s, 1H, H₁₉), 8.02 (t, J = 7.6 Hz, 1H, H₂), 7.77 (t, J = 7.5 Hz, 1H, H₁), 7.52 (d, J = 8.3 Hz, 1H, H₁₆), 7.18 (dd, J = 8.3, 0.9 Hz, 1H, H₁₇), 2.51 (s, 3H, H₂₀). ¹³C NMR = Done but unreadable and it was the same for every compound made with this procedure

2-(6-fluoro-1H-indol-3-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 0.144 13 576 CA 3-75 Precipitate2 (yield = 30%) IC₅₀ (PSA) = 0.048

t_(R) (HPLC) = 3.08 min      MS (ESI+) m/z = 263.1223                [(M + H)⁺] MP = 259-266° C. HRMS (ESI+): calculated for C₁₇H₁₁FN₂Na, m/z = 285.0798; found, 285.0810 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 8.71 (s, 2H, H_(10, 12)), 8.49 (s, 1H, H₁₉), 8.31 (s, 2H, H_(3, 9)), 8.14 (s, 1H, H₆), 7.95 (s, 1H, H2), 7.71 (s, 1H, H₁), 7.40 (d, J = 8.3 Hz, 1H, H₁₆), 7.18 (t, J = 8.5 Hz, 1H, H₁₈). ¹³C NMR = Done but unreadable and it was the same for every compound made with this procedure, even proton spectra looked bad.

2-(6-(trifluoromethyl)-1H-indol-3-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 2.9 13 580 CA 3-78 Precipitate2 (yield = 8%) IC₅₀ (PSA) = Not Tested

t_(R) (HPLC) = 3.50 min      MS (ESI+) m/z = 313.0949                [(M + H)⁺] HRMS (ESI+): calculated for C₁₈H₁₂F₃N₂, m/z = 313.0947; found, 313.0947 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 8.83 (s, 1H, H₁₂), 8.75 (s, 2H, H_(10, 19)), 8.31 (s, 2H, H_(3, 9)), 8.11 (s, 1H, H₆), 7.93 (s, 2H, H_(2, 16)), 7.70 (s, 1H, H₁), 7.58 (d, J = 7.9 Hz, 1H, H₁₈). ¹³C NMR Done but unreadable and it was the same for every compound made with this procedure, even proton spectra looked bad.

2-(7-methyl-1H-indazol-1-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 3.5 13 575 CA 3-90 F4-12 Precipitate IC₅₀ (PSA) = 1.36 (yield = 21%)

t_(R) (HPLC) = 4.54 min      MS (ESI+) m/z = 260.1176                [(M + H)⁺] Mp = 147-152° C. HRMS (ESI+): calculated for C₁₇H₁₄N₃, m/z = 260.1182; found, 260.1172 ¹H NMR (500 MHz, DMSO-d₆): δ (ppm) = 9.42 (s, 1H, H₁₁), 8.69 (d, J = 8.8 Hz, 1H, H₁₀), 8.49 (d, J = 8.8 Hz, 1H, H₉), 8.12 (d, J = 8.0 Hz, 1H, H₆), 8.09 (d, J = 8.5 Hz, 1H, H₃), 7.89 (ddd, J = 8.0, 6.5, 1.0 Hz, 1H, H₂), 7.71-7.65 (m, 2H, H_(1, 9)), 7.14 (d, J = 6.6 Hz, 1H, H₁₇), 7.05 (dd, J = 8.3, 6.7 Hz, 1H, H₁₈), 2.62 (s, 3H, H₂₀). ¹³C NMR (126 MHz, DMSO-d₆): δ (ppm) = 150.74 (C₁₄-arom.), 150.56 (C₈- arom.), 146.38 (C₄-arom.), 140.60 (C₁₀H-arom.), 131.47 (C₂H-arom.), 128.69 (C₆H-arom.), 128.66 (C₃H-arom.), 127.92 (C₅-arom.), 127.89 (C₁₆-arom.), 127.33 (C₁H-arom.), 126.89 (C₁₇H-arom.), 123.64 (C₁₈H-arom.), 122.62 (C₁₅- arom.), 121.65 (C₁₁H-arom.), 119.49 (C₁₉H-arom.), 113.50 (C₉H-arom.), 17.22 (C₂₀H₃).

2-(6-(benzyloxy)-1H-indol-3-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 5.3 13 589 CA 3-94 Precipitate2 (yield = 20%) IC₅₀ (PSA) = Not Tested

t_(R) (HPLC) = 3.66 min      MS (ESI+) m/z = 351.1707                [(M + H)⁺] Mp = 264-269° C. HRMS (ESI+): calculated for C₂₄H₁₉N₂O, m/z = 351.1492; found, 351.1494 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 12.50 (s, 1H, H₁₃), 8.85 (s, 2H, H₁₀), 8.52 (d, J = 5.6 Hz, 1H, H₃), 8.37 (d, J = 8.7 Hz, 1H, H₉), 8.20 (d, J = 7.2 Hz, 2H, H_(6, 19)), 8.00 (t, J = 7.3 Hz, 1H, H₂), 7.75 (t, J = 7.3 Hz, 1H, H₁), 7.51 (d, J = 7.2 Hz, 2H, H_(22, 26)), 7.42 (t, J = 7.4 Hz, 2H, H_(23, 25)), 7.35 (t, J = 7.3 Hz, 1H, H₂₄), 7.19 (d, J = 1.7 Hz, 1H, H₁₆), 7.06 (dd, J = 8.8, 2.0 Hz, 1H, H₁₈), 5.21 (s, 2H, H₂₇). ¹³C NMR Done but unreadable and it was the same for every compound made with this procedure, even proton spectra looked bad.

3-(pyridin-3-yl)-1H-pyrrolo[2,3-c]pyridine (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 4.9 13 581 CA 3-105 Purified (yield = 64%) IC₅₀ (PSA) = Not Tested

t_(R) (HPLC) = 1.45 min       MS (ESI+) m/z = 196.0861                 [(M + H)⁺] Mp = 71-80° C. HRMS (ESI+): calculated for C₁₂H₁₀N₃, m/z = 196.0869; found, 196.0862 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 12.21 (s, 1H, H₁₃), 8.99 (s, 1H, H₃), 8.90 (s, 1H, H₉), 8.49 (s, 1H, H₂), 8.25 (s, 1H, H₇), 8.21 (s, 1H, H₁₄), 8.16- 8.12 (m, 1H, H₅), 7.94 (d, J = 4.0 Hz, 1H, H₁₂), 7.48 (dd, J = 7.7, 4.8 Hz, 1H, H₆). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 147.26 (C₃H-arom.), 146.80 (C₂H-arom.), 137.78 (C₇H-arom.), 134.44 (C₉H-arom.), 133.82 (C₁₀-arom.), 133.41 (C₅H-arom.), 130.47 (C₄-arom.), 129.35 (C₁₁-arom.), 128.95 (C₁₄H- arom.), 123.95 (C₆H-arom.), 113.91 (C₁₂H-arom.), 111.96 (C₁₅-arom.).

3-(pyridin-3-yl)-1H-indazole (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = No Data 13 590 CA 3-106 Precipitate (yield = 45%) IC₅₀ (PSA) = No Data

t_(R) (HPLC) = 2.53 min       MS (ESI+) m/z = 196..0889                 [(M + H)⁺] Mp = 176-179° C. HRMS (ESI+): calculated for C₁₂H₁₀N₃, m/z = 196.0869; found, 196.0871 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 9.21 (d, J = 1.5 Hz, 1H, H₅), 8.62 (dd, J = 4.7, 1.6 Hz, 1H, H₂), 8.38 (td, J = 8.4, 1.8 Hz, 1H, H₃), 8.12 (d, J = 8.2 Hz, 1H, H₁₂), 7.64 (d, J = 8.4 Hz, 1H, H₉), 7.56 (ddd, J = 7.9, 4.8, 0.7 Hz, 1H, H₁), 7.45 (ddd, J = 8.4, 7.2, 0.6 Hz, 1H, H₈), 7.25 (ddd, J = 7.8, 6.6, 0.6 Hz, 1H, H₈). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 148.59 (C₂-arom.), 147.42 (C₅H-arom.), 141.50 (C₁₀-arom.), 140.45 (C₄-arom.), 133.90 (C₃H-arom.), 129.63 (C₁₅-arom.), 126.35 (C₈H-arom.), 124.02 (C₁H-arom ), 121.41 (C₇H- arom.), 120.43 (C₁₂H-arom.), 120.06 (C₁₁-arom), 110.72 (C₉H-arom.).

2-(7-bromo-1H-indol-3-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 0.052 13 582 CA 3-107 F9-17 Precipitate IC₅₀ (PSA) = 0.041 (yield = 20%)

t_(R) (HPLC) = 2.53 min       MS (ESI+) m/z = 323.0177,                 325.1258 [(M + H)⁺] Mp = 178-180° C. HRMS (ES1+): calculated for C₁₇H₁₂BrN₂, m/z = 323.0178, 325.0159; found, 323.0172, 325.0153 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.87 (s, 1H, H₁₃), 8.94 (d, J = 7.9 Hz, 1H, H₁₉), 8.42 (d, J = 2.8 Hz, 1H, H₁₂), 8.29 (d, J = 8.6 Hz, 1H, H₁₀), 8.13 (d, J = 8.7 Hz, 1H, H₉), 8.06 (d, J = 8.4 Hz, 1H, H₃), 7.91 (d, J = 8.0 Hz, 1H, H₆), 7.73 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H, H₂), 7.51 (ddd, J = 7.8, 6.6, 0.6 Hz, 1H, H₁), 7.45 (dd, J = 7.5, 0.5 Hz, 1H, H₁₇), 7.17 (t, J = 7.8 Hz, 1H, H₁₈). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 155.00 (C₈-arom.), 147.65 (C₄- arom.), 135.81 (C₁₀H-arom.), 135.51 (C₁₄H-arom.), 129.43 (C₂H-arom.), 128.78 (C₁₂H-arom.), 128.46 (C₃H-arom.), 127.65 (C₆H-arom.), 127.36 (C₁₅- arom.), 125.96 (C₅-arom.), 125.19 (C₁H-arom.), 124.73 (C₁₇H-arom.), 122.17 (C₁₉H-arom.), 121.76 (C₁₈H-arom.), 119.31 (C₉H-arom.), 116.67 (C₁₁-arom.), 104.34 (C₁₆-arom.).

2-(1H-pyrrolo[2,3-c]pyridin-3-yl)quinoline (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 1.1 13 583 CA 3-109 F22-31 Precipitate IC₅₀ (PSA) = 0.93 (yield = 19%)

t_(R) (HPLC) = 2.52 min       MS (ESI+) m/z = 246.1028                 [(M + H)⁺] Mp = <270° C. HRMS (ESI+): calculated for C₁₆H₁₂N₃, m/z = 246.1026; found, 246.1017 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 12.12 (s, 1H, H,₁₇), 8.85 (d, J = 0.8 Hz, 1H, H₁₃), 8.72 (dd, J = 5.4, 0.9 Hz, 1H, H₁₆), 8.58 (d, J = 2.4 Hz, 1H, H₁₈), 8.31 (m, 2H, H_(10, 11)), 8.09 (d, J = 8.7 Hz, 1H, H₉), 8.07 (d, J = 8.3 Hz, 1H, H₃), 7.92 (d, J = 8.0 Hz, 1H, H₆), 7.74 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H, H₂), 7.52 (ddd, J = 7.8, 7.2, 1.2 Hz, 1H, H₁). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 154.73 (C₈-arom.), 147.73 (C₄- arom.), 139.35 (C₁₁H-arom.), 136.01 (C₁₀H-arom.), 134.88 (C₁₃H-arom.), 134.37 (C₁₄-arom.), 130.89 (C₁₈H-arom.), 129.92 (C₁₅-arom.), 129.51 (C₂H- arom.), 128.46 (C₃H-arom.), 127.69 (C₆H-arom.), 125.97 (C₅-arom.), 125.24 (C₁H-arom.), 119.03 (C₉H-arom.), 116.77 (C₁₆H-arom.), 115.22 (C₁₉-arom.).

tert-butyl 3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

Intermediate LabBook Code CA 3-111 F1-14 (yield = 86%)

t_(R) (HPLC) = 4.66 min       MS (ESI+) m/z = 345.0074                 [(M + H)⁺] ¹H NMR (400 MHz, DMSO-_(d6)): δ (ppm) = 8.44 (dd, J = 4.7, 1.5 Hz, 1H, H₂), 8.03 (s, 1H, H₈), 7.79 (dd, J = 7.9, 1.6 Hz, 1H, H₆), 7.39 (dd, J = 7.9, 4.7 Hz, 1H, H₁), 1.62 (s, 9H, H_(13, 14, 15)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 147.14 (C₁₆ = O), 147.04 (C₄, arom.), 146.16 (C₂H-arom.), 131.54 (C₈H-arom.), 130.04 (C₆H-arom.), 125.25 (C₅-arom.), 120.04 (C₁H-arom.), 84.57 (C₁₂-(CH₃)₃), 63.79 (C₉-arom.), 28.08 (C_(13, 14, 15)-H₃).

3-(1H-pyrrolo[3,2-c]pyridin-3-yl)quinoline (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = Inactive 13 637 CA 3-115 Precipitate (yield = 51%) IC₅₀ (PSA) = Inactive

t_(R) (HPLC) = 2.22 min       MS (ESI+) m/z = 246.1020                 [(M + H)⁺] Mp = 233-239° C. HRMS (ES1+): calculated for C₁₆H₁₂N₃, m/z = 246.1026; found, 246.1016 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 12.04 (s, 1H, H₁₃), 9.43 (s, 1H, H₁₂), 9.37 (d, J = 2.3 Hz, 1H, H₅), 8.76 (d, J = 1.9 Hz, 1H, H₃), 8.31 (d, J = 5.7 Hz, 1H, H₈), 8.19 (d, J = 1.7 Hz, 1H, H₁₄), 8.13 (d, J = 7.6 Hz, 1H, H₁₉), 8.03 (d, J = 8.3 Hz, 1H, H₁₆), 7.72 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H, H₁₇), 7.63 (ddd, J = 8.0, 7.2, 1.2 Hz, 1H, H₁₈), 7.51 (dd, J = 5.7, 0.7 Hz, 1H, H₉). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 150.40 (C₅H-arom.), 146.38 (C₂-arom.), 142.88 (C₁₂H-arom.), 141.29 (C₈H-arom.), 140.94 (C₁₀-arom.), 131.31 (C₃H-arom.), 129.08 (C₁₇H-arom.), 129.04 (C₁₆H-arom.), 128.62 (C₁-arom.), 128.60 (C₁₉H-arom.), 128.35 (C₄-arom.), 127.31 (C₁₈H-arom.), 126.19 (C₁₄H-arom.), 122.63 (C₁₁-arom.), 112.66 (C₁₅-arom.), 107.80 (C₉H- arom.).

3-(5-bromo-2-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridine (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = Inactive 13 638 CA 3-116 Precipitate (yield = quant.) IC₅₀ (PSA) = Inactive

t_(R) (HPLC) = 2.91 min       MS (ESI+) m/z = 303.0118,                 305.0099 [(M + H)⁺] Mp = <270° C. HRMS (ES1+): calculated for C₁₄H₁₂BrN₂O, m/z = 303.0128, 305.0108; found, 303.0119, 305.0100 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 12.03 (s, 1H, H₁₃), 8.82 (d, J = 0.6 Hz, 1H, H₁₂), 8.20 (d, J = 5.7 Hz, 1H, H₈), 7.70 (d, J = 2.0 Hz, 1H, H₁₄), 7.65 (d, J = 2.5 Hz, 1H, H₂), 7.47 (dd, J = 8.8, 2.6 Hz, 1H, H₆), 7.44 (dd, J = 5.7, 1.0 Hz, 1H, H₉), 7.12 (d, J = 8.8 Hz, 1H, H₃), 3.82 (s, 3H, H₁₈). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 155.97 (C₅-arom.), 143.25 (C₁₂H-arom.), 140.41 (C₈H-arom.), 140.06 (C₁₀-arom.), 132.27 (C₃H- arom.), 130.31 (C₆H-arom.), 127.00 (C₁₄H-arom.), 126.07 (C₄-arom.), 123.24 (C₁₁-arom.), 114.24 (C₂H-arom.), 112.46 (C₁-arom.), 110.90 (C₁₅- arom.), 107.57 (C₉H-arom.), 56.13 (C₁₈H₃).

3-(7-bromo-1H-indol-3-yl)quinoline (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 1.13 13 653 CA 3-123 Precipitate (yield = 39%) IC₅₀ (PSA) = 0.29

t_(R) (HPLC) = 3.79 min        MS (ESI+) m/z = 323.0176,                  325.0157 [(M + H)⁺] Mp = 217-223° C. HRMS (ESI+): calculated for C₁₇H₁₂BrN₂, m/z = 323.0178, 325.0159; found, 323.0179, 325.0160 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.86 (s, 1H, H₁₃), 9.33 (d, J = 2.2 Hz, 1H, H₅), 8.66 (d, J = 1.9 Hz, 1H, H₃), 8.12-8.06 (m, 3H, H_(12,14,19)), 8.03 (d, J = 8.3 Hz, 1H, H₁₆), 7.72 (t, J = 8.2 Hz, 1H, H₁₇), 7.63 (t, J = 7.4 Hz, 1H, H₁₈), 7.47 (d, J = 7.5 Hz, 1H, H₈), 7.14 (t, J = 7.8 Hz, 1H, H₇). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 150.63 (C₅H-arom.), 146.32 (C₂-arom.), 135.72 (C₁₀-arom.), 131.21 (C₃H-arom.), 129.11 (C₁₇H-arom.), 128.99 (C₁-arom.), 128.86 (C₁₂H-arom.), 128.57 (C₄-arom.), 128.48 (C₁₉H- arom.), 127.28 (C₁₈H-arom.), 127.19 (C₁₁-arom.), 126.42 (C₁₄H-arom.), 125.01 (C₈H-arom ), 121.96 (C₇H-arom.), 119.28 (C₁₂H-arom.), 114.08 (C₁₅-arom.), 105.30 (C₉-arom.).

3-(7-methyl-1H-indol-3-yl)quinoline (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.92 13 654 CA 3-125 Precipitate (yield = 56%) IC₅₀ (PSA) = 0.16

t_(R) (HPLC) = 3.43 min        MS (ESI+) m/z = 259.1236                  [(M+ H)⁺] Mp = 215-219° C. HRMS (ESI+): calculated for C₁₈H₁₅N₂, m/z =259.1230; found, 259.1234 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.59 (s, 1H, H₁₃), 9.34 (d, J = 2.3 Hz, 1H, H₅), 8.62 (d, J = 2.1 Hz, 1H, H₃), 8.07 (m, 2H, H_(14, 19)), 8.01 (d, J = 8.4 Hz, 1H, H₁₆), 7.92 (d, J = 7.9 Hz, 1H, H₁₂), 7.69 (td, J = 8.4, 1.5 Hz, 1H, H₁₇), 7.61 (td, J = 8.1, 1.2 Hz, 1H, H₁₈), 7.12 (t, J = 7.6 Hz, 1H, H₇), 7.03 (d, J = 7.0 Hz, 1H, H₈), 2.54 (s, 3H, H₂₀). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 150.68 (C₅H-arom.), 146.10 (C₂-arom.), 136.96 (C₁₀-arom.), 130.41 (C₃H-arom.), 129.74 (C₁₇H-arom.), 129.08 (C₁₆H-arom.), 128.72 (C₁-arom.), 128.64 (C₄-arom.), 128.37 (C₁₉H- arom.), 127.19 (C₁₈H-arom.), 125.16 (C₁₁-arom.), 125.01 (C₁₄H-arom.), 122.86 (C₈H-arom.), 121.80 (C₉-arom.), 120.77 (C₇H-arom.), 117.24 (C₁₂H- arom.), 113.06 (C₁₅H-arom.), 17.30 (C₂₀H₃).

7-methyl-3-(pyridin-3-yl)-1H-indole (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 1.66 13 655 CA 3-127 F5 Precipitate (yield = 25%) IC₅₀ (PSA) = 0.61

t_(R) (HPLC) = 2.69 min          MS (ESI+) m/z = 209.1076                    [(M + H)⁺] Mp = 164-166° C. HRMS (ESI+): calculated for C₁₄H₁₃N₂, m/z = 209.1073; found, 209.1075 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.49 (s, 1H, H₁₃), 8.94 (d, J = 1.7 Hz, 1H, H₅), 8.43 (dd, J = 4.7, 1.5 Hz, 1H, H₂), 8.09 (dt, J = 8.0, 1.9 Hz, 1H, H₃), 7.84 (d, J = 2.7 Hz, 1H, H₁₄), 7.70 (d, J = 7.8 Hz, 1H, H₁₂), 7.44 (ddd, J = 7.9, 4.8, 0.6 Hz, 1H), 7.08-6.96 (m, 2H, H_(7, 8)), 2.51 (s, 3H, H₁₆). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 147.81 (C₅H-arom.), 146.63 (C₂H-arom.), 136.86 (C₁₀-arom.), 133.75 (C₃H-arom.), 132.32 (C₄-arom.), 124.99 (C₁₁-arom.), 124.40 (C₁₄H-arom.), 124.28 (C₁H-arom.), 122.66 (C₈H- arom.), 121.74 (C₉-arom.), 120.62 (C₇H-arom.), 116.87 (C₁₂H-arom.), 113.02 (C₁₅-arom.), 17.28 (C₁₆H₃).

tert-butyl 7-(benzyloxy)-3-iodo-1H-indole-1-carboxylate

Intermediate LabBook Code CA 3-128 F1-4 (yield = 88%)

t_(R) (HPLC) = 5.03 min        MS (ESI+) m/z = 450.0575                  [(M + H)⁺] ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 7.84 (s, 1H, H₈), 7.57-7.52 (m, 2H, H_(14, 18)), 7.40-7.27 (m, 4H, H_(1, 15, 16, 17)), 7.11 (d, J = 7.6 Hz, 1H, H₂), 6.98 (dd, J = 7.8, 0.8 Hz, 1H, H₆), 5.25 (s, 2H, H₁₂), 1.50 (s, 9H, H_(21, 22, 23)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 148.11 (C₂₄O), 147.18 (C₃- arom.), 137.44 (C₁₃-arom.), 134.78 (C₅-arom.), 132.89 (C₈H-arom.), 128.67 (C_(15, 17)H-arom.), 128.16 (C₁₆H-arom.), 127.88 (C_(14, 18)H-arom.), 124.89 (C₁H- arom.), 124.45 (C₄-arom.), 114.11 (C₆H-arom.), 109.43 (C₂H-arom.), 84.39 (C₂₀(CH₃)₃), 70.58 (C₁₂H₂), 65.68 (C₉-arom.), 27.68 (C_(21, 22, 23)H₃).

5,8-dibromo-2-(7-methyl-1H-indol-3-yl)quinoline (Procedure 9)

VPC Number LabBook Code IC₅₀ (eGFP) = Inactive 13 679 CA 3-137 F24-30 Precipitate (yield = 20%) IC₅₀ (PSA) = Inactive

t_(R) (HPLC) = 5.30 min           MS (ESI+) m/z = 414.9448,                     416.9430, 418.9416                     [(M + H)⁺] Mp = 218-221° C. HRMS (ESI+): calculated for C₁₈H₁₃Br₂N₂, m/z = 414.9440, 416.942., 418.9402; found, 414.9448, 416.9430, 418.9415 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.84 (s, 1H, H₁₃), 9.01 (d, J = 7.9 Hz, 1H, H₁₉), 8.54 (d, J = 2.9 Hz, 1H, H₁₂), 8.38 (d, J = 9.0 Hz, 1H, H₁₀), 8.33 (d, J = 9.0 Hz, 1H, H₉), 8.04 (d, J = 8.1 Hz, 1H, H₂), 7.73 (d, J = 8.1 Hz, 1H, H₁), 7.16 (t, J = 7.6 Hz, 1H, H₁₈), 7.05 (d, J = 7.1 Hz, 1H, H₁₇), 2.55 (s, 3H, H₂₀). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 157.55 (C₈-arom.), 145.79 (C₄- arom.), 137.28 (C₁₄-arom.), 135.21 (C₁₀H-arom.), 133.70 (C₂H-arom.), 129.80 (C₁₂H-arom.), 129.33 (C₁H-arom.), 126.24 (C₅-arom.), 125.67 (C₁₅-arom.), 124.03 (C₃-arom.), 123.58 (C₁₇H-arom.), 122.06 (C₉H-arom.), 121.65 (C₁₈H- arom.), 121.42 (C₁₆-arom.), 121.18 (C₆-arom., C₁₉H-arom.), 115.73 (C₁₁- arom.), 17.24 (C₂₀H₃).

5-bromo-2-(7-methyl-1H-indol-3-yl)quinoline (Procedure 9)

VPC Number LabBook Code IC₅₀ (eGFP) = Inactive 13 678 CA 3-139 F15-21 Precipitate (yield = 21%) IC₅₀ (PSA) = Inactive

t_(R) (HPLC) = 4.55 min           MS (ESI+) m/z = 337.0363,                     339.0354 [(M + H)⁺] Mp = 200-204° C. HRMS (ESI+): calculated for C₁₈H₁₄BrN₂, m/z = 337.0335, 339.0316; found, 337.0345, 339.0331 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.74 (s, 1H, H₁₃), 8.69 (d, J = 8.0 Hz, 1H, H₁₉), 8.42 (d, J = 3.0 Hz, 1H, H₁₂), 8.36 (dd, J = 9.0, 0.7 Hz, 1H, H₁₀), 8.23 (d, J = 9.0 Hz, 1H, H₉), 8.06 (dt, J = 8.4, 0.9 Hz, 1H, H₁), 7.81 (dd, J = 7.5, 1.0 Hz, 1H, H₃), 7.64 (dd, J = 8.4, 7.6 Hz, 1H, H₂), 7.13 (t, J = 7.6 Hz, 1H, H₁₈), 7.03 (d, J = 7.0 Hz, 1H, H₁₇), 2.54 (s, 3H, H₂₀). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 156.97 (C₈-arom.), 149.20 (C₄- arom.), 137.24 (C₁₄-arom.), 134.47 (C₁₀H-arom.), 130.54 (C₂H-arom.), 129.10 (C₁H-arom.), 129.01 (C₃H-arom.), 128.88 (C₁₂H-arom.), 125.74 (C₅-arom.), 125.10 (C₁₅-arom.), 123.32 (C₁₇H-arom.), 121.45 (C₉H-arom.), 121.43 (C₁₆- arom.), 121.37 (C₆-arom.), 121.24 (C₁₈H-arom.), 120.60 (C₁₉H-arom.), 115.71 (C₁₁-arom.), 17.25 (C₂₀H₃).

3-iodo-7-methyl-1-tosyl-1H-indole

Intermediate LabBook Code CA 3-140 P1-3 (yield = 48%)

t_(R) (HPLC) = 5.50 min         MS (ESI+) m/z = 411.9835                   [(M + H)⁺] ¹H NMR (500 MHz, DMSO-d₆): δ (ppm) = 8.07 (s, 1H, H₈), 7.68 (d, J = 8.3 Hz, 2H, H_(13, 17)), 7.41 (d, J = 8.1 Hz, 2H, H_(14, 16)), 7.29-7.21 (m, 2H, H_(6, 1)), 7.17 (d, J = 6.7 Hz, 1H, H₂), 2.49 (s, 3H, H₁₁), 2.35 (s, 3H, H₁₈). ¹³C NMR (126 MHz, DMSO-d₆): δ (ppm) = 145.86 (C₁₅-arom.), 135.85 (C₁₂- arom.), 134.57 (C₅-arom.), 134.23 (C₄-arom.), 133.76 (C₈H-arom.), 130.85 (C_(14, 16)H-arom.), 129.76 (C₂H-arom.), 126.92 (C_(13, 17)H-arom.), 125.12 (C₁H- arom.), 124.81 (C₃-arom.), 120.38 (C₆H-arom.), 69.54 (C₉-arom.), 21.53 (C₁₈H₃), 21.47 (C₁₁H₃).

8-bromo-2-(7-methyl-1H-indol-3-yl)quinoline (Procedure 9)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.156 13 677 CA 3-141 F34-54 Precipitate (yield = 20%) IC₅₀ (PSA) = 0.11

t_(R) (HPLC) = 5.03 min          MS (ESI+) m/z = 337.0361,                    339.0345 [(M + H)⁺] Mp = 214-217° C. HRMS (ESI+): calculated for C₁₈H₁₄BrN₂, m/z = 337.0335, 339.0316; found, 337.0341, 339.0324 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.72 (s, 1H, H₁₃), 9.04 (d, J = 8.0 Hz, 1H, H₁₉), 8.47 (d, J = 3.0 Hz, 1H, H₁₂), 8.30 (d, J = 8.8 Hz, 1H, H₁₀), 8.20 (d, J = 8.7 Hz, 1H, H₉), 8.09 (dd, J = 7.5, 1.3 Hz, 1H, H₂), 7.92 (dd, J = 8.1, 1.2 Hz, 1H, H₆), 7.39 (t, J = 7.8 Hz, 1H, H₁), 7.14 (t, J = 7.4 Hz, 1H, H₁₈), 7.03 (d, J = 7.0 Hz, 1H, H₁₇), 2.54 (s, 3H, H₂₀). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 156.88 (C₈-arom.), 144.96 (C₄- arom.), 137.23 (C₁₄-arom.), 136.61 (C₁₀H-arom.), 133.25 (C₂H-arom.), 128.92 (C₁₂H-arom.), 128.20 (C₆H-arom.), 127.68 (C₅-arom.), 125.91 (C₁H-arom.), 125.77 (C₁₅-arom.), 123.97 (C₃-arom.), 123.36 (C₁₇H-arom.), 121.38 (C₁₈H- arom.), 121.33 (C₁₉H-arom.), 121.23 (C₁₆-arom.), 120.45 (C₉H-arom.), 116.31 (C₁₁-arom.), 17.25 (C₂₀H₃).

3-(naphthalen-2-yl)-1H-pyrrolo[2,3-c]pyridine (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.45 13 675 CA 3-144 Precipitate (yield = 83%) IC₅₀ (PSA) = 0.468

t_(R) (HPLC) = 3.26 min         MS (ESI+) m/z = 245.1334                   [(M + H)⁺] Mp = 243-247° C. HRMS (ESI+): calculated for C₁₇H₁₃N₂, m/z = 245.1073; found, 245.1079 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.99 (s, 1H, H₁₃), 8.86 (s, 1H, H₉), 8.27 (s, 1H, H₃), 8.25 (d, J = 5.2 Hz, 1H, H₇), 8.17 (s, 1H, H₁₄), 8.05 (dd, J = 5.6, 1.0 Hz, 1H, H₁₂), 8.02 (d, J = 8.1 Hz, 1H, H₁₉), 8.00-7.90 (m, 3H, H_(5,6,16)), 7.53 (ddd, J = 8.1, 6.8, 1.4 Hz, 1H, H₁₈), 7.47 (ddd, J = 8.0, 6.9, 1.3 Hz, 1H, H₁₇). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 139.14 (C₇H-arom.), 135.56 (C₉H-arom.), 134.64 (C₁₀-arom.), 134.14 (C₁-arom.), 132.82 (C₄-arom.), 131.87 (C₂-arom.), 129.56 (C₁₁-arom.), 128.76 (C₆H-arom.), 128.43 (C₁₄H- arom.), 128.18 (C₁₉H-arom.), 127.96 (C₁₆H-arom.), 126.72 (C₁₈H-arom.), 126.01 (C₁₇H-arom.), 125.73 (C₅H-arom.), 124.12 (C₃H-arom.), 115.47 (C₁₅- arom.), 114.55 (C₁₂H-arom.).

3-(naphthalen-2-yl)-1H-pyrrolo[2,3-b]pyridine (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.053 13 676 CA 3-146 Precipitate (yield = 61%) IC₅₀ (PSA) = 0.034

t_(R) (HPLC) = 4.50 min          MS (ESI+) m/z = 245.1077                    [(M + H)⁺] Mp = 207-211° C. HRMS (ESI+): calculated for C₁₇H₁₃N₂, m/z = 245.1073; found, 245.1077 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 12.01 (s, 1H, H₁₃), 8.50 (dd, J = 8.0, 1.1 Hz, 1H, H₁₂), 8.32 (dd, J = 4.6, 1.5 Hz, 1H, H₈), 8.27 (s, 1H, H₃), 8.06 (d, J = 2.7 Hz, 1H, H₁₄), 8.00 (d, J = 8.0 Hz, 1H, H₁₉), 7.97-7.92 (m, 2H, H₅, ₆), 7.91 (d, J = 8.0 Hz, 1H, H₁₆), 7.52 (ddd, J = 8.2, 6.9, 1.4 Hz, 1H, H₁₈), 7.47 (ddd, J = 8.0, 6.9, 1.3 Hz, 1H, H₁₇), 7.22 (dd, J = 8.0, 4.6 Hz, 1H, H₇). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 149.69 (C₁₀-arom.), 143.50 (C₈H-arom.), 134.16 (C₁-arom.), 133.12 (C₄-arom.), 131.85 (C₂-arom.), 128.70 (C₆H-arom.), 128.31 (C₁₂H-arom.), 128.17 (C₁₉H-arom.), 127.94 (C₁₆H-arom.), 126.68 (C₁₈H-arom.), 125.89 (C₁₇H-arom.), 125.66 (C₅H- arom.), 124.90 (C₁₄H-arom.), 123.88 (C₃H-arom.), 117.81 (C₁₁-arom.), 116.62 (C₇H-arom.), 114.55 (C₁₅-arom.).

2-(5-bromo-1H-indol-3-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 2.6 13 683 CA 3-147 F36-46 Precipitate IC₅₀ (PSA) = 1.906 (yield = 39%)

t_(R) (HPLC) = 3.60 min       MS (ESI+) m/z = 323.0169,                 325.0153 [(M + H)⁺] Mp = 200-203° C. HRMS (ESI+): calculated for C₁₇H₁₂BrN₂, m/z = 323.0178, 325.0159; found, 323.0184, 325.0169 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.86 (s, 1H, H₁₃), 9.06 (d, J = 2.0 Hz, 1H, H₁₉), 8.42 (d, J = 2.8 Hz, 1H, H₁₂), 8.27 (d, J = 8.5 Hz, 1H, H₁₀), 8.05 (d, J = 8.8 Hz, 1H, H₉), 8.02 (d, J = 9.0 Hz, 1H, H₃), 7.89 (dd, J = 8.1, 1.2 Hz, 1H, H₆), 7.72 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H, H₆), 7.50 (ddd, J = 8.0, 6.9, 1.2 Hz, 1H, H₁), 7.45 (dd, J = 8.4, 0.4 Hz, 1H, H₁₇), 7.34 (dd, J = 8.6, 2.0 Hz, 1H, H₁₇). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 155.03 (C₈-arom.), 147.62 (C₄- arom.), 135.92 (C₁₀H-arom.), 135.83 (C₁₄-arom.), 129.50 (C₂H-arom.), 129.15 (C₁₂H-arom.), 128.36 (C₃H-arom.), 127.67 (C₆H-arom.), 127.30 (C₁₅-arom.), 125.88 (C₅-arom.), 125.12 (C₁H-arom.), 124.71 (C₁₉H-arom.), 124.62 (C₁₇H- arom.), 119.07 (C₉H-arom.), 115.02 (C₁₁-arom.), 113.79 (C₁₈-arom.), 113.07 (C₁₆H-arom.).

3-(1H-indazol-3-yl)quinoline (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 1.4 13 684 CA 4-13 F3-5 (yield = 46%) IC₅₀ (PSA) = 6.609

t_(R) (HPLC) = 3.59 min      MS (ESI+) m/z = 246.1322                [(M + H)⁺] Mp = 212-215° C. HRMS (ESI+): calculated for C₁₆H₁₂N₃, m/z = 246.1026; found, 246.1027 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 13.53 (s, 1H, H₁₃), 9.60 (d, J = 2.2 Hz, 1H, H₅), 8.98 (d, J = 2.0 Hz, 1H, H₃), 8.33 (d, J = 8.2 Hz, 1H, H₁₂), 8.21 (d, J = 7.9 Hz, 1H, H₁₉), 8.09 (d, J = 8.3 Hz, 1H, H₁₆), 7.8.79 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H, H₁₇), 7.71-7.66 (m, 2H, H_(9, 18)), 7.48 (t, J = 7.4 Hz, 1H, H₈), 7.31 (t, J = 7.5 Hz, 1H, H₇). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 149.67 (C₅H-arom.), 147.27 (C₂- arom.), 142.03 (s C₁₀-arom.), 141.01 (C₁-arom.), 132.67 (C₃H-arom.), 129.94 (C₁₇H-arom.), 129.20 (C₁₆H-arom.), 129.01 (C₁₉H-arom.), 128.24 (C₄-arom.), 127.52 (C₁₈H-arom.), 127.29 (C₁₅-arom.), 126.96 (C₈H-arom.), 121.96 (C₇H- arom.), 121.23 (C₁₂H-arom.), 120.81 (C₁₁-arom.), 111.26 (C₉H-arom.).

3-(naphthalen-2-yl)-1H-pyrrolo[3,2-c]pyridine (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = Inactive 13 685 CA 4-15 Precipitate2 (yield = 71%) IC₅₀ (PSA) = Inactive

t_(R) (HPLC) = 3.17 min        MS (ESI+) m/z = 245.1082                  [(M + H)⁺] Mp = <270° C. HRMS (ESI+): calculated for C₁₇H₁₃N₂, m/z = 245.1073; found, 245.1073 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.85 (s, 1H, H₁₃), 9.39 (s, 1H, H₁₂), 8.33 (s, 1H, H₃), 8.28 (d, J = 5.6 Hz, 1H, H₈), 8.05 (d, J = 8.0 Hz, 1H, H₁₉), 8.02-7.94 (m, 3H, H_(4, 6, 14)), 7.92 (d, J = 8.0 Hz, 1H, H₁₆), 7.53 (ddd, J = 8.0, 7.2, 1.6 Hz, 1H, H₁₈), 7.51-7.45 (m, 2H, H_(9, 17)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 142.94 (C₁₂H-arom.), 141.01 (C₈H-arom.), 140.93 (C₁₀-arom.), 134.16 (C₁-arom.), 132.62 (C₄-arom.), 131.97 (C₂-arom.), 128.76 (C₆H-arom.), 128.30 (C₁₉H-arom.), 127.92 (C₁₆H- arom.), 126.71 (C₁₈H-arom.), 126.21 (C₁₇H-arom.), 125.79 (C₅H-arom.), 125.55 (C₁₄H-arom.), 124.55 (C₃H-arom.), 115.92 (C₁₅-arom.), 107.71 (C₉H- arom.).

2-phenyl-1H-benzo[d]imidazole

VPC Number LabBook Code IC₅₀ (eGFP) = Inactive 13 686 CA 4-16 F3-14 Precipitate IC₅₀ (PSA) = Inactive (yield = 22%)

t_(R) (HPLC) = 2.39 min        MS (ESI+) m/z = 195.1040                  [(M + H)⁺] Mp = <270° C. HRMS (ESI+): calculated for C₁₃H₁₁N₂, m/z = 195.0917; found, 195.0919 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 12.91 (s, 1H, H₁₃), 8.22-8.17 (m, 2H, H_(3, 5)), 7.67 (br s, 1H, H₉), 7.59-7.47 (m, 4H, H_(1, 2, 6, 12)), 7.22-7.19 (m, 2H, H_(7, 8)). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 151.19 (C₁₄-arom.), 143.79 (C₁₀- arom.), 134.98 (C₁₁-arom.), 130.15 (C₄-arom.), 129.81 (C₂H-arom.), 128.92 (C_(1, 6)H-arom.), 126.40 (C_(3, 5)H-arom.), 122.50 (C₇H-arom.), 121.64 (C₈H- arom.), 118.85 (C₉H-arom.), 111.30 (C₁₂H-arom.).

2-naphthalen-3-ol-1H-benzo[d]imidazole

VPC Number LabBook Code IC₅₀ (eGFP) = Inactive 13 687 CA 4-17 Precipitate2 (yield = 14%) IC₅₀ (PSA) = Inactive

6 t_(R) (HPLC) = 3.32 min         MS (ESI+) m/z = 261.1080                   [(M + H)⁺] Mp = <270° C. HRMS (ESI+): calculated for C₁₇H₁₃N₂₀, m/z = 261.1022; found, 261.1022 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 13.46 (s, 1H, H₂₀), 13.01 (s, 1H, H₁₃), 8.72 (s, 1H, H₃), 7.90 (d, J = 8.2 Hz, 1H, H₁₉), 7.79 (d, J = 8.4 Hz, 1H, H₁₆), 7.74 (br s, 2H, , H_(9, 12)), 7.51 (t, J = 7.5 Hz, 1H, H₁₇), 7.43 (s, 1H, H₆), 7.39 (t, J = 7.5 Hz, 1H, H₁₈), 7.34 (br s, 2H, H_(7, 8)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 154.60 (C₅-arom.), 151.15 (C₁₄- arom.), 141.03 (C₁₀-arom.), 135.16 (C₂-arom.), 133.41 (C₁₁-arom.), 128.13 (C₁₉H-arom.), 127.65 (C₁₇H-arom.), 126.99 (C₁-arom.), 126.80 (C₃H-arom.), 126.05 (C₁₆H-arom.), 123.77 (C₁₈H-arom.), 123.60 (C₇H-arom.), 122.57 (C₈H-arom.), 118.21 (C₉H-arom.), 115.21 (C₄-arom.), 111.72 (C₁₂H-arom.), 110.80 (C₆H-arom.).

tert-butyl 3-iodo-7-nitro-1H-indole-1-carboxylate

Intermediate LabBook Code CA 4-18 F4-18 (yield = 90%)

t_(R) (HPLC) = 5.24 min     MS (ESI+) m/z = 410.9828                [(M + Na)⁺] ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 8.10 (s, 1H, H₈), 7.99 (dd, J = 7.9, 0.7 Hz, 1H, H₂), 7.78 (dd, J = 7.9, 1.0 Hz, 1H, H₆), 7.56 (t, J = 7.9 Hz, 1H, H₁), 1.56 (s, 9H, H_(13,14,15)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 147.76 (C₁₆O), 138.62 (C₃- arom.), 135.66 (C₅-arom.), 134.29 (C₈H-arom.), 127.30 (C₆H-arom.), 124.77 (C₄-arom.), 124.25 (C₁H-arom.), 121.63 (C₂H-arom.), 86.64 (C₁₂(CH₃)₃), 66.56 (C₉-arom.), 27.76 (C_(13,14,15)H₃).

3-((2H-tetrazol-5-yl)methyl)-1H-indole

VPC Number LabBook Code IC₅₀ (eGFP) = Inactive 13 700 CA 4-21 F3-4 (yield = 66%) IC₅₀ (PSA) = Inactive

t_(R) = (HPLC) = 2.80 min    MS (ESI+) m/z = 200.0936                [(M + H)⁺] Mp = 174-181° C. HRMS (ESI+): calculated for C₁₀H₁₀N₅, m/z = 200.0931; found, 200.0929 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.03 (s, 1H, H₉), 7.43 (d, J = 8.0 Hz, 1H, H₆), 7.38 (d, J = 8.1 Hz, 1H, H₃), 7.27 (d, J = 2.4 Hz, 1H, H₈), 7.09 (ddd, J = 8.0, 7.2, 1.2 Hz, 1H, H₅), 6.98 (ddd, J = 7.9, 7.1, 1.0 Hz, 1H, H₄), 4.38 (d, J = 0.6 Hz, 2H, H₁₀). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 156.20 (C₁₁-arom.), 136.70 (C₂- arom.), 126.98 (C₈H-arom.), 124.34 (C₁-arom.), 121.75 (C₄H-arom.), 119.11 (C₅H-arom.), 118.57 (C₆H-arom.), 112.02 (C₃H-arom.), 108.78 (C₇-arom.), 19.99 (C₁₀H₂).

3-(2H-tetrazol-5-yl)-1H-indole

VPC Number LabBook Code IC₅₀ (eGFP) = Inactive 13 701 CA 4-22 F9-16 (yield = 33%) IC₅₀ (PSA) = Inactive

t_(R) (HPLC) = 2.86 min        MS (ESI+) m/z = 186.2227 Mp = 220-224° C.         [(M + H)⁺] HRMS (ESI+): calculated for C₉H₈N₅, m/z = 186.0774; found, 186.0776 ¹H HRMS (400 MHz, DMSO-d₆): δ (ppm) = 11.88 (s, 1H, H₉), 8.25-8.22 (m, 1H, H₆), 8.11 (d, J = 2.9 Hz, 1H, H₁₁), 7.57-7.53 (m, 1H, H₃), 7.28-7.20 (m, 2H, H_(4,5)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 151.72 (C₁₀-arom.), 136.86 (C₂H-arom.), 127.53 (C₈H-arom.), 124.91 (C₁-arom.), 123.08 (C₄H-arom.), 121.27 (C₅H-arom.), 120.77 (C₆H-arom.), 112.73 (C₃H-arom.), 99.91 (C₇- arom.).

tert-butyl 3-iodo-7-methyl-1H-indole-1-carboxylate

Intermediate LabBook Code CA 4-23 P1-3 (yield = 81%)

t_(R) (HPLC) = 5.78 min     MS (ESI+) m/z = ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 7.88 (s, 1H, H₈), 7.30-7.19 (m, 3H, H_(1,2,6)), 2.54 (s, 3H, H₁₁), 1.61 (s, 9H, H_(14,15,16)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 148.55 (C₁₇O), 134.13 (C₄- arom.), 133.33 (C₅-arom.), 132.74 (C₈H-arom.), 128.83 (C₂H-arom.), 125.22 (C₃-arom.), 124.29 (C₁H-arom.), 119.45 (C₆H-arom.), 84.70 (C₁₃(CH₃)₃), 66.84 (C₉-arom.), 27.90 (C_(14,15,16)H₃), 21.68 (C₁₁H₃).

tert-butyl 3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

Intermediate LaBook Code CA 4-24 F1-6 (yield = 77%)

t_(R) (HPLC) = 4.59        MS (ESI+) m/z = 345.0111                [(M + H)⁺] ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 8.56 (dd, J = 4.7, 1.4 Hz, 1H, H₁), 8.32 (dd, J = 8.3, 1.3 Hz, 1H, H₃), 8.19 (s, 1H, H₈), 7.43 (dd, J = 8.3, 4.7 Hz, 1H, H₂), 1.64 (s, 9H, H_(13,14,15)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 148.26 (C₁₆O), 147.90 (C₄- arom.), 146.39 (C₁H-arom.), 133.51 (C₈H-arom.), 128.04 (C₅-arom.), 122.61 (C₃H-arom.), 120.60 (C₂H-arom.), 85.59 (C₁₂(CH₃)₃), 69.42 (C₉-arom.), 28.05 (C_(13,14,15)H₃).

3-(naphthalen-2-yl)-7-nitro-1H-indole (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.2 13 702 CA 4-27 F20-51 Precipitate3 (yield = IC₅₀ (PSA) = 0.14 56%)

t_(R) (HPLC) = 4.40 min         MS (ESI+) m/z = 289.0915                     [(M + H)⁺] Mp = 166-171° C. HRMS (ESI+): calculated for C₁₈H₁₃N₂O₂, m/z = 289.0972; found, 289.0975 ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 10.13 (s, 1H, H₁₃), 8.38 (d, J = 7.8 Hz, 1H, H₁₂), 8.28 (d, J = 8.1 Hz, 1H, H₈), 8.11 (s, 1H, H₃), 7.99 (d, J = 8.4 Hz, 1H, H₆), 7.95-7.90 (m, 2H, H_(16,19)), 7.78 (dd, J = 8.5, 1.8 Hz, 1H, H₅), 7.67 (d, J = 2.4 Hz, 1H, H₁₄), 7.59-7.50 (m, 2H, H_(17,18)), 7.35 (t, J = 8.0 Hz, 1H, H₇). ¹³C NMR (101 MHz, CDCl₃): δ (ppm) = 133.82 (C₄-arom.), 133.21 (C₉- arom.), 132.41 (C₂-arom.), 131.32 (C₁-arom.), 130.08 (C₁₀-arom.), 129.92 (C₁₁-arom.), 128.67 (C₆H-arom.), 128.16 (C₁₂H-arom.), 127.83 (C₁₉H-arom.), 127.78 (C₁₆H-arom.), 126.48 (C₅H-arom.), 126.42 (C₁₈H-arom.), 126.14 (C₃H-arom.), 125.86 (C₁₇H-arom.), 124.23 (C₁₄H-arom.), 119.88 (C₁₅-arom.), 119.81 (C₇H-arom.), 119.77 (C₈H-arom.).

3-(naphthalen-2-yl)-1H-pyrrolo[3,2-b]pyridine (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.1 13 703 CA 4-28 Precipitate (yield = 84%) IC₅₀ (PSA) = 0.097

t_(R) (HPLC) = 4.28 min        MS (ESI+) m/z = 245.1068                 [(M + H)⁺] Mp = 221-224° C. HRMS (ESI+): calculated for C₁₇H₁₃N₂, m/z = 245.1073; found, 245.1068 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.66 (s, 1H, H₁₄), 8.97 (d, J = 0.8 Hz, 1H, H₃), 8.53 (dd, J = 4.6, 1.5 Hz, 1H, H₇), 8.35 (dd, J = 8.6, 1.7 Hz, 1H, H₅), 8.33 (d, J = 2.9 Hz, 1H, H₁₄), 7.95-7.90 (m, 2H, H_(6,19)), 7.89-7.84 (m, 2H, H_(9,16)), 7.50 (ddd, J = 8.2, 6.9, 1.4 Hz, 1H, H₁₈), 7.44 (ddd, J = 8.0, 6.9, 1.3 Hz, 1H, H₁₇), 7.22 (dd, J = 8.2, 4.6 Hz, 1H, H₈). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 144.11 (C₁₁-arom.), 143.30 (C₇H-arom.), 134.01 (C₁-arom.), 132.82 (C₄-arom.), 131.77 (C₂-arom.), 130.16 (C₁₀-arom.), 128.07 (C_(6,16)H-arom.), 128.06 (C₁₉H-arom.), 127.67 (C₁₄H-arom.), 126.53 (C₁₈H-arom.), 125.51 (C₅H-arom.), 125.34 (C₁₇H- arom.), 123.77 (C₃H-arom.), 119.47 (C₉H-arom.), 117.21 (C₈H-arom.), 114.52 (C₁₅-arom.).

7-bromo-3-(naphthalen-2-yl)-1H-indole (Procedure 10)

LabBook Code CA 4-29 P2 F3-7 (yield = 12%)

t_(R) (HPLC) = 5.13 min       MS (ESI+) m/z = 323.0095,                 325.0076 [(M + H)⁺] ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.70 (s, 1H, H₁₃), 8.24 (s, 1H, H₃), 8.07 (d, J = 8.0 Hz, 1H, H₁₂), 8.00 (d, J = 8.3 Hz, 1H, H₁₉), 7.98 (d, J = 8.6 Hz, 1H, H₆), 7.94-7.89 (m, 3H, H_(5,14,16)), 7.53 (ddd, J = 8.1, 6.7, 1.4 Hz, 1H, H₁₈), 7.48 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H, H₁₇), 7.44 (d, J = 7.4 Hz, 1H, H₈), 7.12 (t, J = 7.8 Hz, 1H, H₇). ¹³C NMR → n.d.

3-(naphthalen-2-yl)-1H-indol-7-amine

LabBook Code CA 4-34 F6-10 (yield = 28%)

t_(R) (HPLC) = 4.04 min       MS (ESI+) m/z = 259.1295                 [(M + H)⁺] ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 8.22 (s, 1H, H₁₃), 8.18 (s, 1H, H₇), 7.96-7.88 (m, 3H, H_(3,6,10)), 7.85 (dd, J = 8.5, 1.7 Hz, 1H, H₉), 7.62 (d, J = 7.9 Hz, 1H, H₁₉₎, 7.57-7.49 (m, 2H, H_(1,2)), 7.36 (s, 1H, H₁₂), 7.21 (t, J = 7.8 Hz, 1H, H₁₈), 6.69 (d, J = 7.5 Hz, 1H, H₁₇). ¹³C NMR → n.d.

tert-butyl 7-methyl-3-((trimethylsilyl)ethynyl)-1H-indole-1-carboxylate

Intermediate LabBook Code CA 4-35 F5-7 (yield = Quant %)

t_(R) (HPLC) = 5.48 min       MS (ESI+) m/z = ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 7.77 (s, 1H, H₈), 7.54 (d, J = 7.6 Hz, 1H, H₆), 7.25 (t, J = 7.5 Hz, 1H, H₁), 7.18 (d, J = 7.3 Hz, 1H, H₂), 2.67 (s, 3H), 1.66 (s, 9H), 0.33 (s, 9H). ¹³C NMR (101 MHz, CDCl₃): δ (ppm) = 148.78 (C₂₂O), 134.06 (C₄-arom.), 131.84 (C₅-arom.), 131.67 (C₈H-arom.), 128.58 (C₂H-arom.), 125.44 (C₃- arom.), 123.61 (C₁H-arom.), 117.80 (C₆H-arom.), 103.32 (C₉-arom.), 97.93 (C₁₂≡), 96.91 (C₁₀≡), 83.94 (C₁₈(CH₃)₃), 28.01 (C_(19,20,21)H₃), 22.09 (C₁₁H₃), 0.14 (C_(14,15,16)H₃).

3-([1,1′-biphenyl]-4-yl)-7-methyl-1H-indole (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 3.815 13 733 CA 4-38 Precipitate (yield = 25%) IC₅₀ (PSA) = 0.919

t_(R) (HPLC) = 4.50 min        MS (ESI−) m/z = 282.1207 [(M + H)⁻] Mp = 199-202° C. HRMS (ESI−): calculated for C₂₁H₁₆N, m/z = 282.1288; found, 282.1286 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.38 (s, 1H, H₁₃), 7.84-7.79 (m, 2H, H_(3,5)), 7.78-7.70 (m, 6H, H_(1,6,12,14,18,22)), 7.52-7.46 (m, 2H, H_(19,21)), 7.40-7.34 (m, 1H, H₂₀), 7.04 (t, J = 7.2 Hz, 1H, H₇), 6.98 (d, J = 7.0 Hz, 1H, H₈), 2.52 (s, 3H, H₁₇). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 140.51 (C₁₆-arom.), 137.29 (C₂- arom.), 136.90 (C₁₀-arom.), 135.75 (C₄-arom.), 129.40 (C_(19,21)H-arom.), 127.57 (C₂₀H-arom.), 127.43 (C_(1,6)H-arom.), 127.33 (C_(3,5)H-arom.), 126.79 (C_(18,22)H-arom.), 125.14 (C₁₁-arom.), 123.85 (C₁₄H-arom.), 122.44 (C₈H- arom.), 121.62 (C₉-arom.), 120.37 (C₇H-arom.), 117.16 (C₁₂H-arom.), 116.06 (C₁₅-arom.), 17.31 (C₁₇H₃).

3-([1,1′-biphenyl]-4-yl)-1H-pyrrolo[2,3-b]pyridine (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 4.08 13 715 CA 4-39 Precipitate3 (yield = 51%) IC₅₀ (PSA) = 0.35

t_(R) (HPLC) = 4.23 min        MS (ESI−) m/z = 271.1232                  [(M + H)⁺] Mp = <270° C. HRMS (ESI+): calculated for C₁₉H₁₅N₂, m/z = 271.1230; found, 271.1232 ¹H NMR (500 MHz, DMSO-d₆): δ (ppm) = 11.97 (s, 1H, H₁₃), 8.35 (d, J = 7.9 Hz, 1H, H₁₂), 8.30 (dd, J = 4.6, 1.4 Hz, 1H, H₈), 7.96 (d, J = 2.6 Hz, 1H, H₁₄), 7.84 (d, J = 8.3 Hz, 2H, H_(3,5)), 7.79-7.71 (m, 4H, H_(1,6,17,21)), 7.49 (t, J = 7.7 Hz, 2H, H_(20,18)), 7.38 (t, J = 7.4 Hz, 1H, H₁₉), 7.19 (dd, J = 7.9, 4.6 Hz, 1H, H₇). ¹³C NMR (126 MHz, DMSO-d₆): δ (ppm) = 149.60 (C₁₀-arom.), 143.42 (C₈- arom.), 140.39 (C₁₆-arom.), 137.73 (C₂-arom.), 134.78 (C₄-arom.), 129.43 (C_(18,20)H-arom.), 128.02 (C₁₂H-arom.), 127.68 (C₁₉H-arom.), 127.55 (C_(1,6)H- arom.), 127.11 (C_(3,5)H-arom.), 126.84 (C_(17,21)-arom.), 124.41 (C₁₄H-arom.), 117.74 (C₁₁H-arom.), 116.57 (C₇H-arom.), 114.24 (C₁₅-arom.).

3-(4-bromophenyl)-1H-pyrrolo[2,3-b]pyridine (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.067 13 716 CA 4-40 Precipitate (yield = 37%) IC₅₀ (PSA) = 0.058

t_(R) (HPLC) = 3.96 min          MS (ESI−) m/z = 273.0029,                     275.0010 [(M + H)⁺] Mp = 262-266° C. HRMS (ESI+): calculated for C₁₃H₁₀BrN₂, m/z = 273.0022, 275.0002; found, 273.0024, 275.0005 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 12.00 (s, 1H, H₁₃), 8.30-8.27 (m, 2H, H_(8,12)), 7.95 (d, J = 2.7 Hz, 1H, H₁₄), 7.72-7.68 (m, 2H, H_(1,6)), 7.63- 7.59 (m, 2H, H_(3,5)), 7.20-7.15 (m, 1H, H₇). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 149.54 (C₁₀-arom.), 143.52 (C₈H-arom.), 134.83 (C₄-arom.), 132.14 (C_(3,5)H-arom.), 128.60 (C_(1.6)H-arom.), 127.89 (C₁₂H-arom.), 124.70 (C₁₄H-arom.), 118.79 (C₂-arom.), 117.47 (C₁₁- arom.), 116.64 (C₇H-arom.), 113.46 (C₁₅-arom.).

3-([1,1′-biphenyl]-3-yl)-1H-pyrrolo[2,3-b]pyridine (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 11.01 13 734 CA 4-48 Precipitate (yield = 39%) IC₅₀ (PSA) = 4.129

t_(R) (HPLC) = 4.34 min         MS (ESI−) m/z = 271.1226                  [(M + H)⁺] Mp = 182-185° C. HRMS (ESI+): calculated for C₁₉H₁₅N₂, m/z = 271.1230; found, 271.1227 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.97 (s, 1H, H₁₃), 8.34 (dd, J = 8.0, 1.5 Hz, 1H, H₁₂), 8.30 (dd, J = 4.6, 1.5 Hz, 1H, H₈), 8.01 (s, 1H, H₁₄), 7.95 (d, J = 0.7 Hz, 1H, H₃), 7.80-7.75 (m, 2H, H_(17,21)), 7.74-7.71 (m, 1H, H₅), 7.57-7.47 (m, 4H, H_(2,6,18,20)), 7.43-7.39 (m, 1H, H₁₉), 7.18 (dd, J = 7.9, 4.7 Hz, 1H, H₇). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 149.56 (C₁₀-arom.), 143.39 (C₈H-arom.), 141.37 (C₁-arom.), 140.88 (C₁₆-arom.), 136.18 (C₄-arom.), 129.97 (C₆H-arom.), 129.38 (C_(18,20)H-arom.), 127.94 (C_(12,19)H-arom.), 127.37 (C_(17,21)-arom.), 125.87 (C₅H-arom.), 125.07 (C₃H-arom.), 124.62 (C_(2,14)H- arom.), 117.79 (C₁₁-arom.), 116.59 (C₇H-arom.), 114.66 (C₁₅-arom.).

4-(4-bromothiazol-2-yl)morpholine

Intermediate LabBook Code CA 4-50 Ap Tmt (yield = Quant %)

t_(R) (HPLC) = 3.44 min        MS (ESI+) m/z = 248.9720;                   250.9700 [(M + H)⁺] ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 6.92 (s, 1H, H₂), 3.72-3.67 (m, 4H, H_(8,10)), 3.38-3.34 (m, 4H, H_(7,11)). (¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 171.17 (C₄-arom.), 121.03 (C₁- arom.), 105.37 (C₂H-arom.), 65.72 (C_(8,10)H₂), 48.08 (C_(7,11)H₂).

3-([1,1′-biphenyl]-4-yl)-1H-pyrrolo[3,2-b]pyridine (Procedure 10)

VPC Number LabBook Code (IC₅₀ (eGFP) = 3.86 13 735 CA 4-55 Precipitate (yield = 79%) (IC₅₀ (PSA) = 1.433

(t_(R) (HPLC) = 3.55 min      MS (ESI−) m/z = 271.1169                [(M + H)⁺] (Mp = 254-259° C. HRMS (ESI+): calculated for C₁₉H₁₅N₂, m/z = 271.1230; found, 271.1225 (¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.62 (s, 1H, H₁₃), 8.48 (dd, J = 4.6, 1.5 Hz, 1H, H₇), 8.43-8.39 (m, 2H, H_(3,5)), 8.24 (s, 1H, H₁₄), 7.85 (dd, J = 8.2, 1.5 Hz, 1H, H₉), 7.72 (m, 4H, H_(1,6,17,21)), 7.49 (m, 2H, H_(18,20)), 7.39- 7.35 (m, 1H, H₁₉), 7.20 (dd, J = 8.2, 4.6 Hz, 1H, H₈). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 144.02 (C₁₁-arom.), 143.19 (C₇H-arom.), 140.64 (C₁₆-arom.), 137.19 (C₂-arom.), 134.48 (C₄-arom.), 130.04 (C₁₀-arom.), 129.36 (C_(18,20)H-arom.), 127.50 (C₁₉H-arom.), 127.16 (C₁₄H-arom.), 126.99 (C_(1,6)H-arom.), 126.77 (C_(17,21)H-arom.), 126.69 (C_(3,5)H- arom.), 119.42 (C₉H-arom.), 117.09 (C₈H-arom.), 114.21 (C₁₅-arom.).

3-(4-bromophenyl)-1H-pyrrolo[3,2-b]pyridine (Procedure 10)

VPC Number LabBook Code (IC₅₀ (eGFP) = 0.08 13 737 CA 4-64 Precipitate (yield = 25%) (IC₅₀ (PSA) = 0.037

(t_(R) (HPLC) = 2.84 min      MS (ESI−) m/z = 273.0043,                275.0023 [(M + H)⁺] (Mp = 213-221° C. HRMS (ESI+): calculated for C₁₃H₁₀BrN₂, m/z = 273.0022, 275.0002; found, 273.0015, 274.9995 (¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.66 (s, 1H, H₁₃), 8.46 (dd, J = 4.6, 1.5 Hz, 1H, H₇), 8.32-8.27 (m, 2H, H_(1,6)), 8.24 (s, 1H, H₁₄), 7.84 (dd, J = 8.2, 1.5 Hz, 1H, H₉), 7.61-7.55 (m, 2H, H_(3,5)), 7.19 dd, J = 8.2, 4.6 Hz, 1H, H₈). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 143.76 (C₁₁-arom.), 143.27 (C₇H-arom.), 134.53 (C₄-arom.), 131.61 (C_(3,5)-arom.), 130.02 (C₁₀-arom.), 128.10 (C_(1,6)H-arom.), 127.44 (C₁₄H-arom.), 119.53 (C₉H-arom.), 118.24 (C₂-arom.), 117.19 (C₈H-arom.), 113.32 (C₁₅-arom.).

3-(4-bromophenyl)-7-nitro-1H-indole (Procedure 10)

VPC Number LabBook Code (IC₅₀ (eGFP) = 0.083 13 738 CA 4-65 Precipitate (yield = 12%) (IC₅₀ (PSA) = 0.062

(t_(R) (HPLC) = 4.29 min      MS (ESI−) m/z = 314.9732,                316.9703 [(M + H)⁻] (Mp = 192-196° C. HRMS (ESI−): calculated for C₁₄H₈BrN₂O₂, m/z = 314.9775, 316.9755; found, 314.9769, 316.9748 (¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 12.21 (s, 1H, H₁₃), 8.34 (dd, J = 7.9, 0.8 Hz, 1H, H₁₂), 8.20 (dd, J = 8.0, 0.5 Hz, 1H, H₈), 7.89 (s, 1H, H₁₄), 7.71-7.63 (m, 4H, H_(1,3,5,6)), 7.36 dd, J = 8.0 Hz, 1H, H₇). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 133.24 (C₄-arom.), 132.90 (C₉- arom.), 131.78 (C_(1,6)H-arom.), 129.25 (C_(3,5)H-arom.), 129.11 (C₁₁-arom.), 128.95 (C₁₀H-arom.), 127.65 (C₁₂H-arom.), 126.89 (C₁₄H-arom.), 119.58 (C₇H- arom.), 119.26 (C₂-arom.), 119.13 (C₈H-arom.), 116.42 (C₁₅-arom.).

methyl 3-(4-bromophenyl)-1H-indole-7-carboxylate (Procedure 10)

VPC Number LabBook Code (IC₅₀ (eGFP) = 0.62 13 736 CA 4-74 Precipitate (yield = 36%) (IC₅₀ (PSA) = 0.68

(t_(R) (HPLC) = 4.37 min      MS (ESI−) m/z = 327.9978                [(M + H)⁻] (Mp = 149-155° C. HRMS (ESI−): calculated for C₁₆H₁₁BrNO₂, m/z = 327.9975; found, 327.9978 (¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.49 (s, 1H, H₁₃), 8.16 (d, J = 7.9, Hz, 1H, H₁₂), 7.87 (d, J = 6.8 Hz, 1H, H₈), 7.78 (d, J = 2.6 1H, H₁₄), 7.70-7.67 (m, 2H, H_(3,5)), 7.65-7.61 (m, 2H, H_(1,6)), 7.26 (t, J = 7.7 Hz, 1H, H₇). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 166.39 (C₁₇O), 135.02 (C₁₀- arom.), 134.18 (C₄-arom.), 131.67 (C_(1,6)H-arom.), 128.88 (C_(3,5)H-arom.), 126.54 (C₁₁-arom.), 125.42 (C₁₄H-arom.), 124.83 (C₁₂H-arom.), 124.30 (C₈H-arom.), 119.49 (C₇H-arom.), 118.57 (C₂-arom.), 115.07 (C₁₅-arom.), 113.07 (C₉-arom.), 51.94 (C₂₀H₃).

3-phenyl-1H-pyrrolo[2,3-b]pyridine (Procedure 10)

VPC Number LabBook Code (IC₅₀ (eGFP) = 0.66 13 739 CA 4-75 Precipitate (yield = 54%) (IC₅₀ (PSA) = 0.67

(t_(R) (HPLC) = 3.40 min      MS (ESI+) m/z = 195.0920                [(M + H)⁺] (Mp = 92-94° C. HRMS (ESI+): calculated for C₁₃H₁₁N₂, m/z = 195.0917; found, 195.0919 (¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.90 (s, 1H, H₁₃), 8.30-8.26 (m, 2H, H_(8,12)), 7.87 (d, J = 2.6 Hz, 1H, H₁₄), 7.73 (dd, J = 8.2, 1.1 Hz, 2H, H_(3,5)), 7.45 (dd, J = 8.0, 7.5 Hz, 2H, H_(1,6)), 7.26 (tdd, J = 7.2, 6.0, 1.2 Hz, 1H, H₂), 7.16 (dd, J = 7.9, 4.7 Hz, 1H, H₇). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 149.06 (C₁₀-arom.), 142.87 (C₈H- arom.), 135.05 (C₄-arom.), 128.84 (C_(1,6)H-arom.), 127.43 (C₁₂H-arom.), 126.23 (C_(3,5)H-arom.), 125.63 (C₂H-arom.), 123.67 (C₁₄H-arom.), 117.25 (C₁₁-arom.), 116.00 (C₇H-arom.), 114.25 (C₁₅-arom.).

tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate

Intermediate LabBook Code CA 4-76 F2-6 (yield = 68%)

(t_(R) (HPLC) = 4.99 min    MS (ESI+) m/z = n.d. (¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 8.11-8.06 (m, 1H, H₁₃), 7.88 (s, 1H, H8), 7.87-7.82 (m, 1H, H₆), 7.37-7.32 (m, 1H, H₂), 7.31-7.26 (m, 1H, H₁), 1.64 (s, 9H, H_(21,22,23)), 1.33 (s, 12H, H_(15,16,17,18)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 149.11 (C₂₄O), 135.87 (C₄- arom.), 135.33 (C₈H-arom.), 133.22 (C₅-arom.), 124.86 (C₂H-arom.), 123.48 (C₁H-arom.), 122.66 (C₆H-arom.), 115.06 (C₃H-arom.), 107. 92 (C₉-arom.), 84.79 (C₂₀(CH₃)₃), 83.74 (C_(12,13)(CH₃)₂), 28.07 (C_(21,22,23)H₃), 25.14 (C_(15,16,17,18)H₃).

3-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine (Procedure 10)

VPC Number LabBook Code (IC₅₀ (eGFP) = 0.12 13 740 CA 4-85 Precipitate (yield = 50%) (IC₅₀ (PSA) = 0.12

(t_(R) (HPLC) = 3.59 min      MS (ESI+) m/z = 213.0830                [(M + H)⁺] (Mp = 188-192° C. HRMS (ESI+): calculated for C₁₃H₁₀FN₂, m/z = 213.0823; found, 213.0823 (¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.91 (s, 1H, H₁₃), 8.28 (dd, J = 4.6, 1.3 Hz, 1H, H₁₂), 8.26 (dd, J = 8.0, 1.1 Hz, 1H, H₈), 7.86 (d, J = 2.6 Hz, 1H, H₁₄), 7.77-7.73 (m, 2H, H_(3,5)), 7.29-7.24 (m, 2H, H_(1,6)), 7.16 (dd, J = 7.9, 4.6 Hz, 1H, H₇). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 160.52 (d, J = 242.3 Hz, C₂F- arom.), 148.96 (C₁₀-arom.), 142.92 (C₈H-arom.), 131.49 (d, J = 3.0 Hz, C₄- arom.), 127.99 (d, J = 7.8 Hz, C_(3,5)H-arom.), 127.27 (C₁₂H-arom.), 123.66 (C₁₄H-arom.), 117.15 (C₁₁-arom.), 116.02 (C₇H-arom.), 115.61 (d, J = 21.2 Hz, C_(1,6)H-arom.), 113.28 (C₁₅-arom.).

3-(5-(trifluoromethyl)pyridin-2-yl)-1H-indole (Procedure 10)

VPC Number LabBook Code (IC₅₀ (eGFP) = 0.29 13 741 CA 4-88 Crystals (yield = 22%) (IC₅₀ (PSA) = 0.29

(t_(R) (HPLC) = 4.03 min      MS (ESI+) m/z = 263.0793                [(M + H)⁺] (Mp = 154-157° C. HRMS (ESI+): calculated for C₁₄H₁₀F₃N₂, m/z = 263.0791; found, 263.0789 (¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.77 (s, 1H, H₁₃), 8.94-8.92 (m, 1H, H1), 8.50 (d, J = 7.7 Hz, 1H, H₁₂), 8.32 (d, J = 2.9 Hz, 1H, H₁₄), 8.02-8.04 (m, 2H, , H_(5,6)), 7.49 (d, J = 7.8 Hz, 1H, H₉), 7.23-7.16 (m, 2H, H_(7,8)). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 159.25 (d, J = 1.2 Hz, C₄-arom.), 145.86 (q, J = 4.2 Hz, C₁H-arom.), 137.12 (C₁₀-arom.), 133.25 (q, J = 3.1 Hz, C₆H-arom.), 128.17 (C₁₄H-arom.), 125.13 (C₁₁-arom.), 124.31 (q, J = 271.5 Hz, C₁₆F₃), 122.14 (C₈H-arom.), 121.63 (C₁₂H-arom.), 120.55 (C₇H-arom.), 120.30 (q, J = 32.1 Hz, C₂-arom.), 119.02 (C₅H-arom.), 114.24 (C₁₅-arom.), 111.99 (C₉H-arom.).

tert-butyl 7-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate

Intermediate LabBook Code CA 4-89 F10-24 (yield = 68%)

(t_(R) (HPLC) = 5.20 min     MS (ESI+) m/z = n.d. (¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 7.85 (s, 1H, H₈), 7.71 (d, J = 7.1 1H, H8), 7.87-7.82 (m, 1H, H₆), 7.37-7.32 (m, 1H, H₂), 7.31-7.26 (m, 1H, Hz, 1H, H6), 7.19 (t, J = 7.5 Hz, 1H, H1, 7.11 (d, J = 7.1 Hz, 1H, H2), 2.53 (s, 3H, H₁₉), 1.62 (s, 9H, H_(22,23,24)), 1.33 (s, 12H, H_(15,16,17,18)). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 148.60 (C₂₅O), 137.15 (C₈H- arom.), 134.66 (C₄-arom.), 133.93 (C₅-arom.), 127.27 (C₂H-arom.), 124.23 (C₃-arom.), 123.28 (C₁H-arom.), 119.88 (C₆H-arom.), 107.29 (C₉-arom.), 84.18 (C₂₀(CH₃)₃), 83.18 (C_(12,13)(CH₃)₂), 27.42 (C_(22,23,24)H₃), 24.67 (C_(15,16,17,18)H₃), 21.39 (C₁₉H₃).

3-(2-(trifluoromethyl)phenyl)-1H-indole (Procedure 10)

VPC Number LabBook Code (IC₅₀ (eGFP) = 1.01 13 745 CA 4-95 F4-8 (yield = 50%) (IC₅₀ (PSA) = 0.95

(t_(R) (HPLC) = 4.15 min    MS (ESI+) m/z = 260.0687              [(M + H)⁺] (Mp = 62-67° C. HRMS (ESI+): calculated for C₁₅H₉F₃N₂, m/z = 260.0693; found, 260.0687 (¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.39 (s, 1H, H₁₃), 7.85 (d, J = 7.9 Hz, 1H, H₁), 7.72 (t, J = 7.4 Hz, 1H, H₆), 7.59 (d, J = 7.5 Hz, 1H, H₅), 7.55 (t, J = 7.5 Hz, 1H, H₂), 7.49 (d, J = 8.1 Hz, 1H, H₉), 7.40 (s, 1H, H₁₄), 7.36 (d, J = 7.9 Hz, 1H, H₁₂), 7.16 (t, J = 7.5 Hz, 1H, H₈), 7.04 (t, J = 7.4 Hz, 1H, H₇). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 135.73 C₁₀-arom.), 134.23 (d, J = 1.3 Hz, C₄-arom.), 133.18 (C₅H-arom.), 132.04 (C₆H-arom.), 127.71 (q, J = 28.6 Hz, C₃-arom.), 127.01 (C₁₁-arom.), 126.89 (C₂H-arom.), 126.26 (q, J = 5.4 Hz, C₁H-arom.), 124.40 (d, J = 2.9 Hz, C₁₄H-arom.), 124.39 (q, J = 273.6 Hz, C₁₆F₃), 121.46 (C₈H-arom.), 119.42 (C₇H-arom.), 118.32 (C₁₂H-arom.), 112.44 (C₁₅-arom.), 111.70 (C₉H-arom.).

2,3,4-trifluoro-6-iodoaniline

Intermediate LabBook Code CA 4-100 F6-11 (yield = 36%)

(t_(R) (HPLC) = 3.78 min    MS (ESI+) m/z = 273.9338               [(M + H)⁺] (¹H NMR (600 MHz, CDCl₃): δ (ppm) = 7.33 (ddd, J = 9.3, 7.6, 2.5 Hz, 1H, H₆), 4.07 (s, 2H, H₇). ¹³C NMR (151 MHz, CDCl₃): δ (ppm) = 143.20 (ddd, J = 244.0, 10.8, 2.8 Hz, C₃-arom.), 139.98 (ddd, J = 250.5, 16.1, 13.7 Hz, C₂-arom.), 138.48 (ddd, J = 247.1, 12.6, 3.3 Hz, C₁-arom.), 133.43 (dd, J = 11.2, 2.4 Hz, C₄-arom.), 119.96 (dd, J = 20.1, 3.9 Hz, C₆H-arom.), 73.21 (ddd, J = 8.2, 4.5, 2.1 Hz, C₅- arom.).

2-(5,6,7-trifluoro-1H-indol-3-yl)quinoline

LabBook Code (IC₅₀ (eGFP) = 1.01 CA 4-101 F4-6 (yield = 13%) (IC₅₀ (PSA) = 0.95

(t_(R) (HPLC) = 4.32 min     MS (ESI+) m/z = 299.0820               [(M + H)⁺] HRMS (ESI+): calculated for C₁₇H₁₀F₃N₂, m/z = 299.0791; found, 299.0791 (¹H NMR (600 MHz, CDCl₃): δ (ppm) = 9.99 (s, 1H, H₁₅), 8.21 (d, J = 8.4 Hz, 1H, H₁₀), 8.12 (d, J = 8.1 Hz, 1H, H₃), 7.87 (d, J = 8.4 Hz, 1H, H₉), 7.84 (d, J = 8.4 Hz, 1H, H₆), 7.77 (t, J = 7.5 Hz, 1H, H₂), 7.57 (t, J = 7.3 Hz, 1H, H₁), 7.23 (ddd, J = 9.7, 6.5, 1.6 Hz, 1H, H₁₉), 7.12 (s, 1H, H₁₄). ¹³C NMR (151 MHz, CDCl₃): δ (ppm) = 143.30 (C₈-arom.), 147.32 (C₄- arom.), 146.70 (dd, J = 240.3, 12.2 Hz, C₁₆-arom.), 138.72 (C₁₃-arom.), 137.53 (ddd, J = 249.3, 13.6, 4.5 Hz, C₁₇-arom.), 136.93 (ddd, J = 244.8, 17.1, 11.3 Hz, C₁₆-arom.), 136.35 (C₁₀-arom.), 129.70 (C₂H-arom.), 128.58 (C₃H- arom.), 127.22 (C₆H-arom.), 127.06 (C₅-arom.), 126.14 (C₁H-arom.), 124.01 (dd, J = 6.9, 5.5 Hz, C₁₂-arom.), 121.44 (dd, J = 7.7, 2.9 Hz, C₁₁-arom.), 117.52 (C₉H-arom.), 101.92 (m, C_(14,19)H-arom.).

7-(7-methyl-1H-indol-3-yl)quinoline (Procedure 10)

VPC Number LabBook Code (IC₅₀ (eGFP) = 0.76 13 744 CA 4-102 Precipitate (yield = 32%) (IC₅₀ (PSA) = 0.75

(t_(R) (HPLC) = 2.94 min        MS (ESI+) m/z = 259.1272                 [(M + H)⁺] (Mp = 199-201° C. HRMS (ESI+): calculated for C₁₈H₁₅N₂, m/z = 259.1230; found, 259.1228 (¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.54 (s, 1H, H₁₃), 8.89 (dd, J = 4.2, 1.7 Hz, 1H, H₁₉), 8.34 (dd, J = 8.2, 0.9 Hz, 1H, H₁₇), 8.30 (s, 1H, H₃), 8.04-8.00 (m, 2H, H_(5,6)), 7.98 (d, J = 2.4 Hz, 1H, H₁₄), 7.87 (d, J = 8.0 Hz, 1H, H₁₂), 7.47 (dd, J = 8.2, 4.2 Hz, 1H, H₁₈), 7.10 (t, J = 7.5 Hz, 1H, H₈), 7.02 (d, J = 7.0 Hz, 1H, H₈), 2.54 (s, 3H, H₁₆). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 150.65 (C₁₉H-arom.), 148.56 (C₁-arom.), 137.35 (C₄-arom.), 136.61 (C₁₀-arom.), 135.55 (C₁₇H-arom.), 128.24 (C₆H-arom.), 126.41 (C₅H-arom.), 125.92 (C₂-arom.), 124.71 (C₁₄H- arom.), 124.62 (C₁₁-arom.), 124.05 (C₃H-arom.), 122.23 (C₈H-arom.), 121.36 (C₉-arom.), 120.40 (C₇H-arom.), 120.28 (C₁₈H-arom.), 116.64 (C₁₂H-arom.), 115.27 (C₁₅-arom.), 16.83 (C₁₆H₃).

tert-butyl 3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

Intermediate LabBook Code CA 4-104 F1-21 (yield = 83%)

(t_(R) (HPLC) = 4.07 min     MS (ESI+) m/z = 345.0106               [(M + H)⁺] (¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 8.56 (dd, J = 4.7, 1.4 Hz, 1H, H₁), 8.32 (dd, J = 8.3, 1.3 Hz, 1H, H₃), 8.19 (s, 1H, H₈), 7.43 (dd, J = 8.3, 4.7 Hz, 1, H₂), 1.64 (s, 9H, H_(13,14,15)). ¹³C NMR = n.d.

3-(4-(trifluoromethyl)phenyl)-1H-indole (Procedure 10)

VPC Number LabBook Code (IC₅₀ (eGFP) = 0.38 13 743 CA 4-105 F8-16 (yield = 51%) (IC₅₀ (PSA) = 0.39

(t_(R) (HPLC) = 4.34 min      MS (ESI+) m/z = 262.0850               [(M + H)⁺] (Mp = 126-129° C. HRMS (ESI+): calculated for C₁₅H₁₁F₃N, m/z = 262.0838; found, 262.0850 (¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.59 (s, 1H, H₁₃), 7.94 (d, J = 8.2 Hz, 3H, H_(3,5,12)), 7.90 (d, J = 2.6 Hz, 1H, H₁₄), 7.76 (d, J = 8.2 Hz, 2H, H_(1,6)), 7.50 (d, J = 8.0 Hz, 1H, H₉), 7.22-7.18 (m, 1H, H₈), 7.17-7.13 (m, 1H, H₇). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 140.18 (d, J = 0.8 Hz, C₄-arom.), 137.04 (C₁₀-arom.), 126.48 (C_(3,5)H-arom.), 125.58 (q, J = 3.7 Hz, C_(1,6)H-arom.), 125.25 (d, J = 31.7 Hz, C₂-arom.), 125.00 (C₁₄H-arom.), 124.66 (C₁₁H-arom.), 124.62 (q, J = 271.5 Hz, C₁₆F₃), 121.76 (C₈H-arom.), 120.11 (C₇H-arom.), 118.92 (C₁₂H-arom.), 114.12 (C₁₅-arom.), 112.19 (C₉H-arom.).

1-methyl-5-(naphthalen-2-yl)-1H-indole (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 2.0 13 756 CA 4-108 Precipitate (yield = 45%) IC₅₀ (PSA) = 1.49

t_(R) (HPLC) = 4.56 min            MS (ESI+) m/z = 258.1260                     [(M + H)⁺] Mp = 200-204° C. HRMS (ESI+): calculated for C₁₉H₁₆N, m/z = 258.1277; found, 258.1276 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 8.21 (d, J = 0.7 Hz, 1H, H₇), 8.00- 7.97 (m, 3H, H_(6,10,16)), 7.93 (d, J = 8.0 Hz, 1H, H₃), 7.91 (dd, J = 8.5, 1.7 Hz, 1H, H₉), 7.64 (dd, J = 8.5, 1.6 Hz, 1H, H₁₄), 7.57 (d, J = 8.5 Hz, 1H, H₁₃), 7.54 (t, J = 7.3 Hz, 1H, H₁), 7.49 (t, J = 7.3 Hz, 1H, H₂), 7.39 (d, J = 3.0 Hz, 1H, H₁₈), 6.53 (d, J = 3.0 Hz, 1H, H₁₉), 3.85 (s, 3H, H₂₀). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 139.02 (C₈-arom.), 136.09 (C₁₁- arom.), 133.52 (C₅-arom.), 131.70 (C₄-arom.), 131.12 (C₁₅-arom.), 130.43 (C₁₈H-arom.), 128.68 (C₁₂-arom.), 128.20 (C₁₀H-arom.), 127.95 (C₆H-arom.), 127.41 (C₃H-arom.), 126.19 (C₁H-arom.), 125.62 (C₂H-arom.), 125.50 (C₉H- arom.), 124.60 (C₇H-arom.), 120.61 (C₁₄H-arom.), 118.75 (C₁₆H-arom.), 110.20 (C₁₃H-arom.), 100.86 (C₁₉H-arom.), 32.58 (C₂₀H₃).

3-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[3,2-b]pyridine (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 13 CA 4-109 Precipitate (yield = 69%) IC₅₀ (PSA) =

t_(R) (HPLC) = 2.89 min           MS (ESI+) m/z = 263.0792                    [(M + H)⁺] Mp = 223-226° C. HRMS (ESI+): calculated for C₁₄H₁₀F₃N₂, m/z = 263.0791; found, 263.0790 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.78 (s, 1H, H₁₁), 8.55 (d, J = 8.2 Hz, 2H, H_(3,5)), 8.49 (dd, J = 4.5, 1.3 Hz, 1H, H₁₃), 8.36 (s, 1H, H₇), 7.87 (dd, J = 8.2, 1.4 Hz, 1H, H₁₅), 7.75 (d, J = 8.3 Hz, 2H, H_(2,6)), 7.22 (dd, J = 8.2, 4.5 Hz, 1H, H₁₄). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 143.41 (C₉-arom.), 143.07 (C₁₃H- arom.), 139.02 (d, J = 0.9 Hz, C₄-arom.), 129.64 (C₁₀-arom.), 128.07 (C₇H- arom.), 125.77 (C_(3,5)H-arom.), 125.16 (q, J = 3.7 Hz, C_(2,6)H-arom.), 125.14 (q, J = 31.6 Hz, C₁-arom.), 124.67 (q, J = 271.4 Hz, C₁₆F₃), 119.23 (C₁₅H-arom.), 116.93 (C₁₄H-arom.), 112.60 (C₈-arom.).

3-(2-bromophenyl)-1H-pyrrolo[3,2-b]pyridine (Procedure 10)

LabBook Code CA 4-110 Precipitate2 (yield = 37%)

t_(R) (HPLC) = 2.61 min         MS (ESI+) m/z = 273.0018,                    274.9998 [(M + H)⁺] HRMS (ESI+): calculated for C₁₃H₁₀BrN₂, m/z = 2273.0022, 275.0002; found, 273.0018, 274.9998 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.61 (s, 1H, H₁₁), 8.37 (d, J = 4.4 Hz, 1H, H₁₃), 7.99 (s, 1H, H₇), 7.90 (d, J = 7.7 Hz, 1H, H₅), 7.85 (d, J = 8.1 Hz, 1H, H₁₅), 7.74 (d, J = 7.9 Hz, 1H, H₂), 7.45 (t, J = 7.5 Hz, 1H, H₆), 7.24 (t, J = 7.6 Hz, 1H, H₁), 7.18 (dd, J = 8.1, 4.5 Hz, 1H, H₁₄). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 143.75 (C₉-arom.), 142.71 (C₁₃H- arom.), 134.57 (C₄-arom.), 132.93 (C₂H-arom.), 132.70 (C₅H-arom.), 128.75 (C₇H-arom.), 128.29 (C₁₀-arom.), 127.86 (C₁H-arom.), 127.21 (C₆H-arom.), 122.57 (C₃-arom.), 118.89 (C₁₅H-arom.), 116.70 (C₁₄H-arom.), 113.74 (C₈- arom.).

6-(7-methyl-1H-indol-3-yl)benzo[d]thiazole (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = Inactive 13 757 CA 4-114 F9-15 Precipitate (yield = 27%) IC₅₀ (PSA) = Inactive

t_(R) (HPLC) = 4.02 min           MS (ESI+) m/z = 265.0787                    [(M + H)⁺] Mp = 183-185° C. HRMS (ESI+): calculated for C₁₆H₁₃N₂S, m/z = 265.0794; found, 265.0793 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.42 (s, 1H, H₁₄), 9.32 (s, 1H, H₈), 8.48 (d, J = 0.8 Hz, 1H, H₆), 8.12 (d, J = 8.5 Hz, 1H, H₃), 7.90 (dd, J = 8.5, 1.6 Hz, 1H, H₄), 7.84-7.80 (m, 2H, H_(13,18)), 7.05 (t, J = 7.5 Hz, 1H, H₁₇), 6.99 (d, J = 7.0 Hz, 1H, H₁₆), 2.52 (s, 3H, H₁₉). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 154.81 (C₈H-arom.), 150.95 (C₁- arom.), 136.43 (C₁₀-arom.), 134.50 (C₂-arom.), 133.67 (C₅-arom.), 125.37 (C₄H- arom.), 124.63 (C₁₁-arom.), 123.87 (C₁₃H-arom.), 123.01 (C₃H-arom.), 122.07 (C₁₆H-arom.), 121.15 (C₁₅-arom.), 119.98 (C₁₇H-arom.), 119.15 (C₆H-arom.), 116.70 (C₁₈H-arom.), 115.44 (C₁₂-arom.), 16.81 (C₁₉H₃).

2-(quinolin-5-yl)thiazole

LabBook Code CA 4-116 F14-17 (yield = 36%)

t_(R) (HPLC) = 2.95 min        MS (ESI+) m/z = 213.0468                  [(M + H)⁺] ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 9.31 (d, J = 8.7 Hz, 1H, H₆), 9.00 (dd, J = 4.0, 1.6 Hz, 1H, H₄), 8.18 (d, J = 8.4 Hz, 1H, H₁₀), 8.13 (d, J = 3.3 Hz, 1H, H₁₂), 8.05 (d, J = 7.2 Hz, 1H, H₈), 7.98 (d, J = 3.3 Hz, 1H, H₁₁), 7.89 (dd, J = 8.3, 7.4 Hz, 1H, H₉), 7.67 (dd, J = 8.7, 4.1 Hz, 1H, H₅). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 165.68 (C₁₄-arom.), 150.97 (C₄H- arom.), 148.04 (C₂-arom.), 143.95 (C₁₂H-arom.), 134.04 (C₆H-arom.), 131.25 (C₁₀H-arom.), 130.17 (C₇-arom.), 129.09 (C₉H-arom.), 128.68 (C₈H-arom.), 124.92 (C₁-arom.), 122.51 (C₅H-arom.), 121.55 (C₁₁H-arom.).

5-(7-methyl-1H-indol-3-yl)benzo[d]thiazole (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = Inactive 13 758 CA 4-118 F18-25 (yield = 68%) IC₅₀ (PSA) = Inactive

t_(R) (HPLC) = 3.93 min         MS (ESI+) m/z = 265.0790                  [(M + H)⁺] Mp = 133-136° C. HRMS (ESI+): calculated for C₁₆H₁₃N₂S, m/z = 265.0794; found, 265.0790 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.43 (s, 1H, H₁₅), 9.41 (s, 1H, H₈), 8.39 (d, J = 1.1 Hz, 1H, H₆), 8.20 (d, J = 8.3 Hz, 1H, H₃), 7.87 (dd, J = 8.4, 1.5 Hz, 1H, H₄), 7.86 (d, J = 2.6 Hz, 1H, H₁₃), 7.79 (d, J = 8.0 Hz, 1H, H₁₈), 7.06 (t, J = 7.5 Hz, 1H, H₁₇), 6.99 (d, J = 7.0 Hz, 1H, H₁₆), 2.54 (s, 3H, H₁₉). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 156.22 (C₈H-arom.), 153.99 (C₂- arom.), 136.44 (C₁₀-arom.), 134.47 (C₅-arom.), 130.24 (C₁-arom.), 124.84 (C₄H- arom.), 124.70 (C₁₁-arom.), 123.76 (C₁₃H-arom.), 122.52 (C₃H-arom.), 122.05 (C₁₆H-arom.), 121.21 (C₁₅-arom.), 120.04 (C₆H-arom.), 120.01 (C₁₇H-arom.), 116.45 (C₁₈H-arom.), 115.56 (C₁₂-arom.), 16.83 (C₁₉H₃).

5-(7-methyl-1H-indol-3-yl)benzo[d]oxazole (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.3 13 759 CA 4-119 Precipitate (yield = 26%) IC₅₀ (PSA) = 0.27

t_(R) (HPLC) = 3.87 min          MS (ESI+) m/z = 249.1041                   [(M + H)⁺] Mp = 171-172° C. HRMS (ESI+): calculated for C₁₆H₁₃N₂O, m/z = 249.1022; found, 249.1016 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.35 (s, 1H, H₁₄), 8.75 (s, 1H, H₈), 8.03 (d, J = 1.3 Hz, 1H, H₆), 7.82 (d, J = 8.4 Hz, 1H, H₃), 7.77 (dd, J = 8.4, 1.6 Hz, 1H, H₄), 7.75 (d, J = 2.6 Hz, 1H, H₁₃), 7.72 (d, J = 8.0 Hz, 1H, H₁₈), 7.03 (t, J = 7.5 Hz, 1H, H₁₇), 6.98 (d, J = 7.0 Hz, 1H, H₁₆), 2.52 (s, 3H, H₁₉). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 154.42 (C₈H-arom.), 147.60 (C₁- arom.), 140.40 (C₂-arom.), 136.31 (C₁₀-arom.), 132.98 (C₅-arom.), 124.75 (C₄H- arom.), 124.70 (C₁₁-arom.), 123.40 (C₁₃H-arom.), 121.95 (C₁₆H-arom.), 121.11 (C₁₅-arom.), 119.88 (C₁₇H-arom.), 117.38 (C₆H-arom.), 116.32 (C₁₈H-arom.), 115.79 (C₁₂-arom.), 111.18 (C₃H-arom.), 16.81 (C₁₉H₃).

2-(7-methyl-1H-indol-3-yl)benzo[d]thiazole (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.1 13 760 CA 4-120 F12-18 Precipitate (yield = IC₅₀ (PSA) = 0.52 30%)

t_(R) (HPLC) = 4.02 min           MS (ESI+) m/z = 265.0788                      [(M + H)⁺] Mp = 179-182° C. HRMS (ESI+): calculated for C₁₆H₁₃N₂S, m/z = 265.0794; found, 265.0790 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.95 (s, 1H, H₅), 8.25 (d, J = 2.9 Hz, 1H, H₄), 8.22 (d, J = 7.9 Hz, 1H, H₉), 8.06 (d, J = 7.9 Hz, 1H, H₁₃), 7.97 (d, J = 8.1 Hz, 1H, H₁₆), 7.49 (t, J = 7.6 Hz, 1H, H₁₅), 7.37 (t, J = 7.6 Hz, 1H, H₁₄), 7.17 (t, J = 7.5 Hz, 1H, H₈), 7.07 (d, J = 7.1 Hz, 1H, H₇), 2.54 (s, 3H, H₁₀). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 162.90 (C₁₈-arom.), 153.68 (C₁₂- arom.), 136.26 (C₁-arom.), 133.03 (C₁₁-arom.), 128.52 (C₄H-arom.), 126.09 (C₁₅H-arom.), 124.32 (C₂-arom.), 124.17 (C₁₄H-arom.), 123.25 (C₇H-arom.), 121.71 (C₁₃H-arom.), 121.63 (C₆-arom.), 121.53 (C₁₆H-arom.), 121.30 (C₈H- arom.), 118.22 (C₉H-arom.), 110.81 (C₃-arom.), 16.74 (C₁₀H₃).

3-(3-bromophenyl)-1H-pyrrolo[3,2-b]pyridine (Procedure 10)

LabBook Code CA 4-124 Precipitate (yield = 30%)

t_(R) (HPLC) = 2.71 min          MS (ESI+) m/z = 273.0006,                    274.9986 [(M + H)⁺] HRMS (ESI+): calculated for C₁₃H₁₀BrN₂, m/z = 273.0022, 275.0002; found, 273.0023, 275.0003 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.69 (s, 1H), 8.65 (s, 1H), 8.49 (d, J = 3.5 Hz, 1H), 8.29 (d, J = 2.8 Hz, 1H), 8.28-8.25 (m, 1H), 7.85 (dd, J = 8.2, 1.0 Hz, 1H), 7.38-7.34 (m, 2H), 7.20 (dd, J = 8.1, 4.6 Hz, 1H). ¹³C NMR = n.d.

4-bromo-2-(7-methyl-1H-indol-3-yl)thiazole (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.045 13766 CA 4-125 F7-11 (yield = 43%) IC₅₀ (PSA) = 0.02

t_(R) (HPLC) = 4.00 min         MS (ESI+) m/z = 292.9743,                  294.9724 [(M + H)⁺] Mp = 127-130° C. HRMS (ESI+): calculated for C₁₂H₁₀BrN₂S, m/z = 292.9743, 294.9722; found, 292.9743, 294.9723 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.86 (s, 1H, H₅), 8.16 (s, 1H, H₄), 7.93 (d, J = 7.7 Hz, 1H, H₉), 7.62 (s, 1H, H₁₄), 7.13 (t, J = 7.3 Hz, 1H, H₈), 7.04 (d, J = 6.6 Hz, 1H, H₇), 2.52 (s, 3H, H₁₀). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 164.43 (C₁₁-arom.), 136.06 (C₁- arom.), 126.82 (C₄H-arom.), 123.71 (C₁₃-arom.), 123.69 (C₂-arom.), 123.09 (C₇H-arom.), 121.67 (C₆H-arom.), 121.19 (C₈H-arom.), 117.45 (C₉H-arom.), 113.69 (C₁₄H-arom.), 110.13 (C₃-arom.), 16.71 (C₁₀H₃).

tert-butyl 6-fluoro-3-iodo-1H-indole-1-carboxylate

Intermediate LabBook Code CA 4-126 F1-6 (yield = 95%)

t_(R) (HPLC) = 4.80 min        MS (ESI+) m/z = n.d. ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 7.90 (s, 1H, H₈), 7.82 (dd, J = 10.2, 2.0 Hz, 1H, H₃), 7.40 (dd, J = 8.7, 5.3 Hz, 1H, H₆), 7.24 (td, J = 9.1, 2.4 Hz, 1H, H₁), 1.64 (s, 9H, H_(14,15,16)). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 160.69 (d, J = 239.6 Hz, C₂- arom.), 147.88 (C₁₇O), 134.17 (d, J = 13.2 Hz, C₄-arom.), 130.75 (d, J = 3.8 Hz, C₈H-arom.), 128.47 (C₅-arom.), 122.61 (d, J = 10.3 Hz, C₆H-arom.), 111.66 (d, J = 24.4 Hz, C₁H-arom.), 101.61 (d, J = 28.9 Hz, C₃H-arom.), 84.90 (C₁₃), 66.05 (C₉-arom.), 27.55 (s C_(14,15,16)H₃).

-   -   3-(4-methoxyphenyl)-1H-pyrrolo[3,2-b]pyridine (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 13 CA 4-127 Precipitate (yield = 89%) IC₅₀ (PSA) =

t_(R) (HPLC) = 2.54 min          MS (ESI+) m/z = 225.1037                   [(M + H)⁺] Mp = 202-206° C. HRMS (ESI+): calculated for C₁₄H₁₃N₂O, m/z = 225.1022; found, 2251027 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.42 (s, 1H, H₁₁), 8.43 (dd, J = 4.5, 1.5 Hz, 1H, H₁₃), 8.22-8.18 (m, 2H, H_(2,6)), 8.04 (d, J = 2.8 Hz, 1H, H₇), 7.80 (dd, J = 8.2, 1.5 Hz, 1H, H₁₅), 7.16 (dd, J = 8.1, 4.5 Hz, 1H, H₁₄), 7.01- 6.96 (m, 2H, H_(3,5)), 3.79 (s, 3H, H₁₇). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 157.12 (C₁-arom.), 143.36 (C₉- arom.), 142.39 (C₁₃H-arom.), 129.37 (C₁₀-arom.), 127.28 (C₄-arom.), 127.01 (C_(2,6)H-arom.), 125.43 (C₇H-arom.), 118.69 (C₁₅H-arom.), 116.38 (C₁₄H- arom.), 114.10 (C₈-arom.), 113.76 (C_(3,5)H-arom.), 55.01 (C₁₇H₃).

6-(7-methyl-1H-indol-3-yl)isoquinoline (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = inactive 13765 CA 4-128 Precipitate (yield = 34%) IC₅₀ (PSA) = inactive

t_(R) (HPLC) = 3.01 min          MS (ESI+) m/z = 259.1230                   [(M + H)⁺] Mp = 222-225° C. HRMS (ESI+): calculated for C₁₈H₁₅N₂, m/z = 259.1230; found, 259.1231 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.59 (s, 1H, H₅), 9.25 (s, 1H, H₁₆), 8.47 (d, J = 5.7 Hz, 1H, H₁₂), 8.27 (s, 1H, H₁₇), 8.15-8.09 (m, 2H, H_(19,20)), 8.01 (d, J = 2.7 Hz, 1H, H₄), 7.95 (d, J = 8.0 Hz, 1H, H₉), 7.88 (d, J = 5.8 Hz, 1H, H₁₃), 7.11 (t, J = 7.5 Hz, 1H, H₉), 7.03 (d, J = 7.0 Hz, 1H, H₇), 2.54 (s, 3H, H₁₀). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 151.69 (C₁₆H-arom.), 143.10 (C₁₂H-arom.), 138.20 (C₁₈-arom.), 136.65 (C₁-arom.), 136.13 (C₁₄-arom.), 127.81 (C₂₀H-arom.), 127.20 (C₁₉H-arom.), 126.42 (C₁₅-arom.), 125.23 (C₄H- arom.), 124.55 (C₂-arom.), 122.35 (C₇H-arom.), 121.35 (C₆-arom.), 121.17 (C₁₇H-arom.), 120.35 (C₈H-arom.), 120.20 (C₁₃H-arom.), 116.98 (C₉H- arom.), 115.17 (C₃-arom.), 16.81 (C₁₀H₃).

2-(6-fluoro-1H-indol-3-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 0.1 13764 CA 4-131 F25-28 Precipitate (yield = IC₅₀ (PSA) = 0.082 5%)

t_(R) (HPLC) = 3.07 min           MS (ESI+) m/z = 263.0968                      [(M + H)⁺] Mp = 195-198° C. HRMS (ESI+): calculated for C₁₇H₁₂FN₂, m/z = 263.0979; found, 263.0981 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.71 (s, 1H, H₁₇), 8.90 (dd, J = 8.7, 5.9 Hz, 1H, H₁₆), 8.36 (d, J = 2.6 Hz, 1H, H₁₈), 8.27 (d, J = 8.7 Hz, 1H, H₁₀), 8.06-8.02 (m, 2H, H_(3,9)), 7.90 (d, J = 7.7 Hz, 1H, H₆), 7.72 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H, H₆), 7.49 (ddd, J = 7.8, 6.6, 0.6 Hz, 1H, H₁), 7.26 (dd, J = 9.8, 2.4 Hz, 1H, H₁₃), 7.07 (td, J = 9.6, 2.4 Hz, 1H, H₁₁). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 159.13 (d, J = 235.8 Hz, C₁₂- arom.), 155.18 (C₈-arom.), 147.68 (C₄-arom.), 137.16 (d, J = 12.5 Hz, C₁₄- arom.), 135.69 (C₁₀H-arom.), 129.38 (C₂H-arom.), 128.39 (C₃H-arom.), 128.32 (d, J = 2.8 Hz, C₁₈H-arom.), 127.63 (C₆H-arom.), 125.87 (C₅-arom.), 125.02 (C₁H-arom.), 123.78 (d, J = 9.8 Hz, C₁₆H-arom.), 122.40 (C₁₅-arom.), 119.08 (C₉H-arom.), 115.58 (C₁₉-arom.), 108.64 (d, J = 23.6 Hz, C₁₁H- arom.), 97.73 (d, J = 25.4 Hz, C₁₃H-arom.).

A person of skill in the art based on the general knowledge in the art and the information provided herein would be able to synthesize the compounds described herein or modify the compounds described herein.

eGFP Cellular Transcription Assay

AR transcriptional activity was assayed as previously described (Tavassoli, P. et al. Rapid, non-destructive, cell-based screening assays for agents that modulate growth, death, and androgen receptor activation in prostate cancer cells. Prostate 2007, 67, 416-426). Briefly, stably transfected eGFP-expressing LNCaP human prostate cancer cells (LN-ARR2PB-eGFP) containing an androgen responsive probasin-derived promoter (ARR2PB) were grown in phenol red free RPMI 1640 supplemented with 5% CSS. After 5 days, the cells were plated into a 96-well plate (35,000 cells/well) with 0.1 nM of the synthetic androgen R1881 and increasing concentrations (0-100 μM) of compound. The cells were incubated for three days and the fluorescence was then measured (excitation 485 nm, emission 535 nm). The viability of these cells was assayed by MTS cell proliferation assay (CellTiter 961™ Aqueous One Solution Reagent, Promega™).

Structure Solution and Refinement

The ternary complex structure was solved by molecular replacement using the Phaser program (McCoy, A. J. et al. Phaser crystallographic software. J Appl Crystallogr 2007, 40, 658-674) and the coordinate of an apo-protein structure of AR-testosterone complex (Protein Data Bank entry 2AM9) as the search model. The structures were refined with iterative cycles of manual density fitting with COOT and refinement with Refmac (Murshudov, G. N. et al. Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr D Biol Crystallogr. 1997, 53, 240-255). The extra density of testosterone was clearly observed at the initial refinement step. A characteristic electron density of the compound was observed at the BF3 binding site.

Heterologous Expression of Androgen Receptor

The AR ligand binding domain was expressed and purified as previously described (Estebanez-Perpina, E. et al. Proc. Nat. Acad. Sci. USA(2007) 104:16074-16079).

eGFP Cellular AR Transcription Assay: AR transcriptional activity was assayed as previously described.²¹ Briefly, stably transfected eGFP-expressing LNCaP human prostate cancer cells (LN-ARR2PBeGFP) containing an androgen-responsive probasin-derived promoter (ARR2PB) were grown in phenol-red-free RPMI 1640 supplemented with 5% CSS. After 5 days, the cells were plated into a 96-well plate (35,000 cells/well) with 0.1 nM R1881 and increasing concentrations (0-100 μM) of compound. The cells were incubated for 3 days, and the fluorescence was then measured (excitation, 485 nm; emission, 535 nm). The viability of these cells has been assayed by the MTS cell proliferation assay (CellTiter 961 Aqueous One Solution Reagent, Promega) according to the instructions of the manufacturer.

Prostate Surface Antigen assay: The evaluation of PSA excreted into the media was performed in parallel to the eGFP assay using the same plates (see above description). After the cells were incubated for 3 days 150 μl of the media was taken from each well, and added to 150 μl of PBS. PSA levels were then evaluated using Cobas e 411 analyzer instrument (Roche Diagnostics) according to the manufacturer's instructions.

EXAMPLES Example 1 Virtual Screen for Potential BF3 Binders

Using a previously described (Axerio-Cilies, P. et al. Inhibitors of Androgen Receptor Activation Function-2 (AF2) Site Indentified Through Virtual Screening. J Med Chem 2011 54(18):6197-205), consensus-based in silico methodology we conducted a virtual screen of ˜10 million purchasable chemical substances from the ZINC database to identify BF3-specific binders (also one NCI compound). The screening method used a combination of large-scale docking, ligand-based QSAR modeling, pharmacophore search, molecular field analysis, molecular-mechanic and molecular dynamic simulations (Cherkasov, A. et al. Progressive docking: a hybrid QSAR/docking approach for accelerating in silico high throughput screening. J Med Chem. 2006, 49, 7466-7478; Cherkasov, A. et al. ‘Inductive’ charges on atoms in proteins: comparative docking with the extended steroid benchmark set and discovery of a novel SHBG ligand. J Chem Inf Model 2005, 45, 1842-1853; and Santos-Filho, O. A. and Cherkasov, A. Using molecular docking, 3D-QSAR, and cluster analysis for screening structurally diverse data sets of pharmacological interest. J Chem Inf Model 2008, 48, 2054-2065). The results from each stage of this multi-parametric approach were compiled and the compounds were ranked using a consensus scoring procedure. The highest ranked compounds were visualized and initial candidates, predicted to have a high potential for binding to the BF3 pocket, were selected for empirical testing.

Example 2 Cell-Based Testing

All compounds were screened for their ability to inhibit AR transcriptional activity using a non-destructive, cell-based eGFP screening assay (Tavassoli, P. et al. Rapid, non-destructive, cell-based screening assays for agents that modulate growth, death, and androgen receptor activation in prostate cancer cells. Prostate 2007, 67, 416-426). In this assay, the expression of eGFP is under the control of an androgen responsive probasin-derived promoter and can quantify AR transcriptional activity. From the compounds tested, 7 showed sub-μM IC50 values in the eGFP assay. Compounds that exhibited non-specific cellular toxicity were removed from further analysis. The most potent molecules had IC₅₀'s ranging in from 0.11 to 50 μM range (TABLE 3). Some compounds were also tested in the PSA assay (TABLE 3).

TABLE 3 Structural and experimental data for the AR BF3 interactors. eGFP Internal IC₅₀ PSA IC₅₀ Number ZINC Number STRUCTURE (μM) (μM) 13555 Synthetic derivative

Inactive Not tested 13557 Synthetic derivative

Inactive Not tested  9039 Synthetic derivative

>200 Not tested 13312 ZINC00298052

200.0 Not tested  9040 Synthetic derivative

39.13 Not tested 13309 ZINC01234071

27.2 Not tested  9034 Synthetic derivative

20 Not tested 13551 Synthetic derivative

15.5 Not tested 13550 Synthetic derivative

11.75 Not tested  9026 Synthetic derivative

11.67 Not tested 13544 Synthetic derivative

11.4 13561 Synthetic derivative

10.7 Not tested 13310 ZINC00297221

103 Not tested 13232 ZINC02992016

10 Not Determined  9028 Synthetic derivative

10 Not tested 13050 ZINC03365783

9.725 Not Determined 13300 ZINC00270867

9.3 6.76 13299 ZINC00499454

8.2 Not tested  9027 Synthetic derivative

7.721 Not tested 13538 Synthetic derivative

7.7 13304 ZINC00270887

7.3 4.54 13258 ZINC18191564

6.8 Not tested 13559 Synthetic derivative

6.6 Not tested 13512 Synthetic derivative

6.0 13542 Synthetic derivative

5.7  9125 ZINC30469682

5.2 2.4 13186 ZINC00513042

5 Not Determined 13224 ZINC04106386

5 Not Determined 13524 Synthetic derivative

4.9 6.65 13508 Synthetic derivative

4.8 2.7 13250 ZINC03149578

4.7 Not tested 13530 Synthetic derivative

4.7 1.60 13303 ZINC00270884

4.5 Not tested 13503 Synthetic derivative

4.5 Not tested 13257 ZINC12345945

4.2 Not tested 13502 Synthetic derivative

4.1 Not tested  9037 Synthetic derivative

4.093 Not tested 13243 ZINC00253227

3.9 Not tested 13543 Synthetic derivative

3.7 3.19 13424 ZINC12346351

3.7 3.58 13516 Synthetic derivative

3.6 Not tested  6054 ZINC08718421

3.4 Not Determined 13505 Synthetic derivative

3.4 Not tested 13522 Synthetic derivative

3.4 2.19 13029 ZINC00210926

3.221 Not Determined 13548 Synthetic derivative

3.21 4.24  9128 ZINC47424036

3.2 3.5 13525 Synthetic derivative

3.1 7.09 13511 Synthetic derivative

3.0 1.9 13216 ZINC06025409

2.8 Not Determined 13532 Synthetic derivative

2.8 3.10 13260 ZINC49491101

2.7 Not tested 13416 ZINC01869964

2.7 2.32 13509 Synthetic derivative

2.6 3.1  9043 Synthetic derivative

2.503 Not tested 13202 ZINC01768344

2.5 Not Determined 13510 Synthetic derivative

2.5 1.54 13540 Synthetic derivative

2.5 Not tested 13411 ZINC04106386

2.4 2.4 13560 Synthetic derivative

2.3 7.5 13214 ZINC26472877

2.2 Not Determined 13235 ZINC01037115

2.2 1.01 13536 Synthetic derivative

2.2 2.521 13556 Synthetic derivative

2.112 2.18 13127 ZINC00392643

2.1 0.11 13261 ZINC48546225

2.1 Not tested 13215 ZINC05504717

2 Not Determined 13504 Synthetic derivative

2.0 1.69 13167 NSC105329

1.9 1.25 13206 ZINC04962047

1.8 Not Determined 13145 ZINC34603778

1.7 2.46 13549 Synthetic derivative

1.7 2.57 13245 ZINC00555700

1.7 1.69 13036 ZINC14961821

1.602 Not Determined 13166 ZINC01723993

1.6 2.12 13558 Synthetic derivative

1.6 2.1 13535 Synthetic derivative

1.5 1.873 13164-B ZINC02046058

1.3 1.59 13500 Synthetic derivative

1.23 0.41 13254 ZINC18191551

1.2 Not tested 13410 ZINC04106383

1.2 2.03 13552 Synthetic derivative

1.125 1.14 13423 ZINC18191568

1.1 1.2 13222 ZINC02718340

0.95 0.74 13247 ZINC48090221

0.9 0.43 13412 ZINC02718340

0.9 1.23 13534 Synthetic derivative

0.8 1.251 13434 ZINC00069102

0.8 0.73 13164-A ZINC02046058

0.77 0.67 13220 ZINC48544111

0.7 Not Determined 13225 ZINC18191568

0.7 0.9 13537 Synthetic derivative

0.7 0.8057 13436 ZINC00068959

0.6 0.4 13554 Synthetic derivative

0.59 0.67 13541 Synthetic derivative

0.5 0.94 13255 ZINC18191553

0.5 0.46 13163-A ZINC02043019

0.48 0.16 13163-B ZINC02043019

0.48 0.24 13256 ZINC05848672

0.4 0.13 13521 Synthetic derivative

0.4 0.26 13427 ZINC00588219

0.4 0.31 13259 ZINC18191559

0.3 0.25 13506 Synthetic derivative

0.18 0.6 13226 ZINC18191571

0.11 0.076 13562 Known see U.S. Pat. No. 6,207,679

0.06 0.14 13566 Known see U.S. Pat. No. 6,207,679

0.004 0.011 13567 Synthetic derivative

0.200 0.230 13568 Synthetic derivative

1.300 1.560 13569 Synthetic derivative

1.600 Not tested 13570 Synthetic derivative

20.000 Not tested 13571 Synthetic derivative

1.100 Not tested 13573 Synthetic derivative

0.560 Not tested 13574 Synthetic derivative

2.570 Not tested 13576 Synthetic derivative

0.144 0.048 13577 Synthetic derivative

3.200 1.730 13579 Synthetic derivative

0.101 0.043 13580 Synthetic derivative

2.900 Not tested 13582 Synthetic derivative

0.052 0.041 13585 Synthetic derivative

0.110 0.039 13587 Synthetic derivative

0.760 0.530 13589 Synthetic derivative

5.300 Not tested 13591 Synthetic derivative

0.042 0.085 13592 Synthetic derivative

1.590 1.220 13593 Synthetic derivative

0.198 0.130 13594 Synthetic derivative

0.166 0.099 13595 Synthetic derivative

0.177 Not tested 13596 Synthetic derivative

Inactive Inactive 13597 Synthetic derivative

0.236 0.132 13598 Synthetic derivative

Inactive Inactive 13599 Synthetic derivative

Inactive Inactive 13600 Synthetic derivative

1.249 0.929 13601 Synthetic derivative

0.233 0.165 13602 Synthetic derivative

0.240 0.182 13603 Synthetic derivative

0.633 0.339 13604 Synthetic derivative

Inactive Inactive 13605 Synthetic derivative

Inactive Inactive 13606 Synthetic derivative

1.649 1.427 13607 Synthetic derivative

0.168 0.087 13608 Synthetic derivative

Inactive Inactive 13609 Synthetic derivative

Inactive Inactive 13610 Synthetic derivative

0.032 0.013 13611 Synthetic derivative

0.297 0.121 13612 Synthetic derivative

1.44 0.813 13613 Synthetic derivative

11.540 1.738 13614 Synthetic derivative

1.117 0.597 13615 Synthetic derivative

Inactive Inactive 13616 Synthetic derivative

Inactive Inactive 13617 Synthetic derivative

Inactive Inactive 13618 Synthetic derivative

0.194 0.13 13619 Synthetic derivative

2.170 Not tested 13620 Synthetic derivative

Inactive Inactive 13621 Synthetic derivative

0.02 0.008 13622 Synthetic derivative

0.1 0.075 13623 Synthetic derivative

Inactive Inactive 13624 Synthetic derivative

0.100 0.042 13625 Synthetic derivative

1.900 1.230 13626 Synthetic derivative

2.700 1.650 13627 Synthetic derivative

1.500 1.160 13628 Synthetic derivative

0.800 0.610 13629 Synthetic derivative

4.900 1.780 13630 Synthetic derivative

0.600 0.430 13631 Synthetic derivative

Inactive Inactive 13632 Synthetic derivative

Inactive Inactive 13633 Synthetic derivative

6.000 Not tested 13634 Synthetic derivative

5.000 Not tested 13635 Synthetic derivative

Inactive Inactive 13636 Synthetic derivative

Inactive Inactive 13637 Synthetic derivative

Inactive Inactive 13638 Synthetic derivative

Inactive Inactive 13639 Synthetic derivative

0.549 0.544 13640 Synthetic derivative

12.670 Not tested 13641 Synthetic derivative

0.132 0.403 13642 Synthetic derivative

0.033 0.025 13643 Synthetic derivative

0.1638 0.156 13644 Synthetic derivative

3.000 Not tested 13645 Synthetic derivative

0.261 0.247 13646 Synthetic derivative

0.179 0.224 13647 Synthetic derivative

Inactive Inactive 13648 Synthetic derivative

Inactive Inactive 13649 Synthetic derivative

Inactive Inactive 13650 Synthetic derivative

1.631 Not tested 13651 Synthetic derivative

0.404 Not tested 13652 Synthetic derivative

3.54 1.76 13653 Synthetic derivative

1.13 0.29 13654 Synthetic derivative

0.92 0.16 13655 Synthetic derivative

1.66 0.61 13656 Synthetic derivative

0.99 0.46 13657 Synthetic derivative

Inactive Inactive 13658 Synthetic derivative

2.85 2.21 13659 Synthetic derivative

Inactive Inactive 13660 Synthetic derivative

2.5 1.89 13661 Synthetic derivative

Inactive Inactive 13662 Synthetic derivative

Inactive Inactive 13663 Synthetic derivative

Inactive Inactive 13664 Synthetic derivative

Inactive Inactive 13665 Synthetic derivative

0.27 0.21 13666 Synthetic derivative

Inactive Inactive 13667 Synthetic derivative

Inactive Inactive 13668 Synthetic derivative

Inactive Inactive 13669 Synthetic derivative

Inactive Inactive 13670 Synthetic derivative

Inactive Inactive 13671 Synthetic derivative

Inactive Inactive 13672 Synthetic derivative

Inactive Inactive 13673 Synthetic derivative

Inactive Inactive 13674 Synthetic derivative

0.075 0.051 13677 Synthetic derivative

0.156 0.11 13678 Synthetic derivative

Inactive Inactive 13679 Synthetic derivative

Inactive Inactive 13680 Synthetic derivative

0.8 Not tested 13681 Synthetic derivative

2.5 1.7 13682 Synthetic derivative

0.89 0.99 13683 Synthetic derivative

2.6 1.906 13684 Synthetic derivative

1.4 6.609 13685 Synthetic derivative

Inactive Inactive 13686 Synthetic derivative

Inactive Inactive 13687 Synthetic derivative

Inactive Inactive 13688 Synthetic derivative

0.069 0.068 13689 Synthetic derivative

Inactive Inactive 13690 Synthetic derivative

Inactive Inactive 13691 Synthetic derivative

0.4 0.48 13692 Synthetic derivative

0.1 0.082 13693 Synthetic derivative

0.11 0.12 13694 Synthetic derivative

0.07 0.067 13695 Synthetic derivative

0.069 0.087 13696 Synthetic derivative

0.042 0.042 13697 Synthetic derivative

0.029 0.029 13698 Synthetic derivative

0.041 0.041 13699 Synthetic derivative

0.073 0.073 13700 Synthetic derivative

Inactive Inactive 13701 Synthetic derivative

Inactive Inactive 13702 Synthetic derivative

0.21 0.14 13704 Synthetic derivative

0.35 0.169 13705 Synthetic derivative

Inactive Inactive 13706 Synthetic derivative

Inactive Inactive 13707 Synthetic derivative

Inactive Inactive 13708 Synthetic derivative

0.29 0.29 13709 Synthetic derivative

Inactive Inactive 13710 Synthetic derivative

0.23 0.25 13711 Synthetic derivative

Inactive Inactive 13712 Synthetic derivative

Inactive Inactive 13713 Synthetic derivative

0.037 13714 Synthetic derivative

Inactive Inactive 13717 Synthetic derivative

0.49 0.33 13718 Synthetic derivative

0.37 0.11 13719 Synthetic derivative

0.11 0.13 13720 Synthetic derivative

Inactive Inactive 13721 Synthetic derivative

Inactive Inactive 13722 Synthetic derivative

Inactive Inactive 13723 Synthetic derivative

Inactive Inactive 13724 Synthetic derivative

Inactive Inactive 13725 Synthetic derivative

Inactive Inactive 13726 Synthetic derivative

Inactive Inactive 13727 Synthetic derivative

Inactive Inactive 13728 Synthetic derivative

Inactive Inactive 13729 Synthetic derivative

Inactive Inactive 13730 Synthetic derivative

0.149 0.198 13731 Synthetic derivative

0.304 0.255 13732 Synthetic derivative

0.42 Not tested 13733 Synthetic derivative

3.815 0.9194 13736 Synthetic derivative

0.62 0.68 13738 Synthetic derivative

0.083 0.062 13741 Synthetic derivative

0.29 0.29 13742 Synthetic derivative

0.22 0.2 13743 Synthetic derivative

0.38 0.39 13744 Synthetic derivative

0.76 0.75 13745 Synthetic derivative

1.01 0.95 13746 Synthetic derivative

Inactive Inactive 13747 Synthetic derivative

Inactive Inactive 13748 Synthetic derivative

Inactive Inactive 13749 Synthetic derivative

0.29 0.22 13750 Synthetic derivative

Inactive Inactive 13751 Synthetic derivative

Inactive Inactive 13752 Synthetic derivative

0.37 0.26 13753 Synthetic derivative

0.16 0.098 13754 Synthetic derivative

0.09 0.051 13755 Synthetic derivative

0.47 0.47 13757 Synthetic derivative

Inactive Inactive 13758 Synthetic derivative

Inactive Inactive 13759 Synthetic derivative

0.3 0.27 13760 Synthetic derivative

0.1 0.052 13761 Synthetic derivative

0.5481 0.3829 13762 Synthetic derivative

0.4792 0.429 13764 Synthetic derivative

0.1 0.082 13765 Synthetic derivative

Inactive Inactive 13766 Synthetic derivative

0.045 0.020 13769 Synthetic derivative

Inactive Inactive 13770 Synthetic derivative

0.1 0.017 13771 Synthetic derivative

0.2 0.090 13772 Synthetic derivative

0.2 0.172 13773 Synthetic derivative

0.3 0.303 13774 Synthetic derivative

0.7 0.773 13775 Synthetic derivative

3.7 Not tested 13776 Synthetic derivative

0.21 0.19 13777 Synthetic derivative

Not tested Not tested 13778 Synthetic derivative

Not tested Not tested 13779 Synthetic derivative

Not tested Not tested 13780 Synthetic derivative

Not tested Not tested 13781 Synthetic derivative

Not tested Not tested 13782 Synthetic derivative

0.11 Not tested 13783 Synthetic derivative

Not tested Not tested 13784 Synthetic derivative

Not tested Not tested 13785 Synthetic derivative

0.036 Not tested 13786 Synthetic derivative

0.013 Not tested 13787 Synthetic derivative

0.19 Not tested 13788 Synthetic derivative

Not tested Not tested 13507 Synthetic derivative

Not tested Not tested 13513 Synthetic derivative

Not tested Not tested 13514 Synthetic derivative

Not tested Not tested 13515 Synthetic derivative

Not tested Not tested 13517 Synthetic derivative

Not tested Not tested 13518 Synthetic derivative

Not tested Not tested 13519 Synthetic derivative

Not tested Not tested 13520 Synthetic derivative

Not tested Not tested 13523 Synthetic derivative

Not tested Not tested 13526 Synthetic derivative

Not tested Not tested 13527 Synthetic derivative

Not tested Not tested 13531 Synthetic derivative

Not tested Not tested 13539 Synthetic derivative

Not tested Not tested 13545 Synthetic derivative

Not tested Not tested 13546 Synthetic derivative

Not tested Not tested 13547 Synthetic derivative

Not tested Not tested

Where a compound is described as “inactive”, no activity was detected for the compound in the assays on which it was tested.

Although various embodiments of the invention are disclosed herein, many adaptations and modifications may be made within the scope of the invention in accordance with the common general knowledge of those skilled in this art. Such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way. Numeric ranges are inclusive of the numbers defining the range. The word “comprising” is used herein as an open-ended term, substantially equivalent to the phrase “including, but not limited to”, and the word “comprises” has a corresponding meaning. As used herein, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a thing” includes more than one such thing. Citation of references herein is not an admission that such references are prior art to an embodiment of the present invention. The invention includes all embodiments and variations substantially as hereinbefore described and with reference to the examples and drawings. 

What is claimed is:
 1. A compound having the structure of Formula II:

wherein, L₁ is H; L₂ is H, Cl, F or Br; L₃ is H, Cl, F or Br; L₄ is C(O)NHCH₃, CF₃,

L₅ is H; L₆ is H; L₇ is H; L₈ is Cl, F or Br; L₉ is Cl, F or Br; and L₁₀ is Cl, F or Br.
 2. The compound of claim 1, wherein L₂ is H, Cl or F; and L₃ is H, Cl or F.
 3. The compound of claim 1, wherein L₂ is H, Cl or F; L₃ is H, Cl or F; L₈ is Cl or F; L₉ is Cl or F; and L₁₀ is Cl or F.
 4. The compound of claim 1, wherein L₂ is H, Cl or F; L₃ is H, Cl or F; L₈ is F; L₉ is F; and L₁₀ is F.
 5. The compound of claim 1, wherein L₄ is C(O)NHCH₃.
 6. The compound of claim 1, wherein L₄ is CF₃,


7. The compound of claim 1, wherein L₂ is H, Cl or F; L₃ is H, Cl or F; L₄ is C(O)NHCH₃, CF₃,

L₈ is Cl or F; L₉ is Cl or F; and L₁₀ is Cl or F.
 8. The compound of claim 1, wherein L₂ is H, Cl or F; L₃ is H, Cl or F; L₄ is C(O)NHCH₃; L₈ is Cl or F; L₉ is Cl or F; and L₁₀ is Cl or F.
 9. The compound of claim 1, wherein L₂ is H, Cl or F; L₃ is H, Cl or F; L₄ is C(O)NHCH₃ or CF₃; L₈ is Cl or F; L₉ is Cl or F; and L₁₀ is Cl or F.
 10. The compound of claim 1, wherein L₂ is H, Cl or F; L₃ is H, Cl or F; L₄ is C(O)NHCH₃,

L₈ is Cl or F; L₉ is Cl or F; and L₁₀ is Cl or F.
 11. The compound of claim 1, wherein L₂ is H, Cl or F; L₃ is H, Cl or F; L₄ is C(O)NHCH₃, CF₃ or

L₈ is Cl or F; L₉ is Cl or F; and L₁₀ is Cl or F.
 12. The compound of claim 1, wherein the compound is:


13. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable excipient.
 14. The pharmaceutical composition of claim 13, wherein the compound is selected from:


15. A method of modulating AR activity, the method comprising (a) administering a compound of claim 1 to a subject in need thereof.
 16. The method of claim 15, wherein the modulating AR activity is for the treatment of at least one indication selected from the group consisting of: AR-mediated cancer, prostate cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, Taxene resistant triple negative breast cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, and age-related macular degeneration.
 17. The method of claim 16, wherein the modulating AR activity is for the treatment of prostate cancer.
 18. The method of claim 16, wherein the modulating AR activity is for the treatment of Taxene resistant triple negative breast cancer.
 19. The method of claim 16, wherein the modulating AR activity is for the treatment of ovarian cancer.
 20. The method of claim 16, wherein the modulating AR activity is for the treatment of endometrial cancer. 